Method of optimizing efficacy of therapeutic agent

ABSTRACT

Method and device for outputting one or more signals associated with a monitored analyte level of an individual, the one or more signals including a substantially real time monitored analyte level and a rate of change information associated with the monitored analyte level, outputting a carbohydrate intake event indication, determining one or more data associated with one or more therapy information related to the monitored analyte level and the meal event indication, and outputting the determined one or more data over the outputted one or more signals associated with the monitored analyte level and the carbohydrate intake event indication are provided.

CROSS REFERENCE TO RELATED APPLICATION

The present application is a continuation of U.S. application Ser. No.16/116,977, filed Aug. 30, 2018, which is a continuation of U.S.application Ser. No. 12/199,854, filed Aug. 28, 2008, which claimspriority to U.S. Provisional Application No. 60/969,578, filed Aug. 31,2007, each of these applications are incorporated herein by reference intheir entireties.

BACKGROUND

The monitoring of the level of glucose or other analytes, such aslactate or oxygen, in certain individuals is vitally important to theirhealth. High or low levels of glucose or other analytes may havedetrimental effects. The monitoring of glucose is particularly importantto individuals with diabetes, as they must determine when insulin isneeded to reduce glucose levels in their bodies or when additionalglucose is needed to raise the level of glucose in their bodies.

A conventional technique used by many diabetics for personallymonitoring their blood glucose level includes the periodic drawing ofblood, the application of that blood to a test strip, and thedetermination of the blood glucose level using colorimetric,electrochemical, or photometric detection. This technique does notpermit continuous or automatic monitoring of glucose levels in the body,but typically must be performed manually on a periodic basis.Unfortunately, the consistency with which the level of glucose ischecked varies widely among individuals. Many diabetics find theperiodic testing inconvenient and they sometimes forget to test theirglucose level or do not have time for a proper test. In addition, someindividuals wish to avoid the pain associated with the test. Thesesituations may result in hyperglycemic or hypoglycemic episodes. An invivo glucose sensor that continuously or automatically monitors theindividual's glucose level would enable individuals to more easilymonitor their glucose, or other analyte, levels.

A variety of devices have been developed for continuous or automaticmonitoring of analytes, such as glucose, in the blood stream orinterstitial fluid. A number of these devices use electrochemicalsensors which are directly implanted into a blood vessel or in thesubcutaneous tissue of a patient. However, these devices are oftendifficult to reproducibly and inexpensively manufacture in largenumbers. In addition, these devices are typically large, bulky, and/orinflexible, and many can not be used effectively outside of a controlledmedical facility, such as a hospital or a doctor's office, unless thepatient is restricted in his activities.

Some devices include a sensor guide which rests on or near the skin ofthe patient and may be attached to the patient to hold the sensor inplace. These sensor guides are typically bulky and do not allow forfreedom of movement. In addition, the sensor guides or the sensorsinclude cables or wires for connecting the sensor to other equipment todirect the signals from the sensors to an analyzer. The size of thesensor guides and presence of cables and wires hinders the convenientuse of these devices for everyday applications. There is a need for asmall, compact device that can operate the sensor and provide signals toan analyzer without substantially restricting the movements andactivities of a patient.

The patient's comfort and the range of activities that can be performedwhile the sensor is implanted are important considerations in designingextended-use sensors for continuous or automatic in vivo monitoring ofthe level of an analyte, such as glucose. There is a need for a small,comfortable device which can continuously monitor the level of ananalyte, such as glucose, while still permitting the patient to engagein normal activities. Continuous and/or automatic monitoring of theanalyte can provide a warning to the patient when the level of theanalyte is at or near a threshold level. For example, if glucose is theanalyte, then the monitoring device might be configured to warn thepatient of current or impending hyperglycemia or hypoglycemia. Thepatient can then take appropriate actions.

SUMMARY

In one aspect, outputting one or more signals associated with amonitored analyte level of an individual, the one or more signalsincluding a substantially real time monitored analyte level and a rateof change information associated with the monitored analyte level,outputting a carbohydrate intake event indication, determining one ormore data associated with one or more therapy information related to themonitored analyte level and the meal event indication, and outputtingthe determined one or more data over the outputted one or more signalsassociated with the monitored analyte level and the carbohydrate intakeevent indication is provided.

In another aspect, a communication interface configured to receive oneor more data associated with a monitored analyte level, and a processorcoupled to the communication interface, the processor configured todetect a carbohydrate intake event indication, and to detect apredetermined rate of change of the monitored analyte level based on thereceived one or more data associated with the monitored analyte level,where the processor is further configured to disable one or more therapyrelated functions executable by a user when the detected predeterminedrate of change deviates from a predefined threshold level are provided.

The above summary of the present disclosure is not intended to describeeach disclosed embodiment or every implementation of the presentdisclosure. The Figures and the detailed description which follow moreparticularly exemplify these embodiments.

BRIEF DESCRIPTION OF THE DRAWING

The disclosure may be more completely understood in consideration of thefollowing detailed description of various embodiments of the disclosurein connection with the accompanying drawings, in which:

FIG. 1 is a block diagram of one embodiment of a subcutaneous analytemonitor using a subcutaneously implantable analyte sensor, according tothe disclosure;

FIG. 2 is a top view of one embodiment of an analyte sensor, accordingto the disclosure;

FIG. 3A is a cross-sectional view of the analyte sensor of FIG. 2;

FIG. 3B is a cross-sectional view of another embodiment of an analytesensor, according to the disclosure;

FIG. 4A is a cross-sectional view of a third embodiment of an analytesensor, according to the disclosure;

FIG. 4B is a cross-sectional view of a fourth embodiment of an analytesensor, according to the disclosure;

FIG. 5 is an expanded top view of a tip portion of the analyte sensor ofFIG. 2;

FIG. 6 is a cross-sectional view of a fifth embodiment of an analytesensor, according to the disclosure;

FIG. 7 is an expanded top view of a tip-portion of the analyte sensor ofFIG. 6;

FIG. 8 is an expanded bottom view of a tip-portion of the analyte sensorof FIG. 6;

FIG. 9 is a side view of the analyte sensor of FIG. 2;

FIG. 10 is a top view of the analyte sensor of FIG. 6;

FIG. 11 is a bottom view of the analyte sensor of FIG. 6;

FIG. 12 is an expanded side view of one embodiment of a sensor and aninsertion device, according to the disclosure;

FIGS. 13A, 13B, 13C are cross-sectional views of three embodiments ofthe insertion device of FIG. 12;

FIG. 14 is a cross-sectional view of one embodiment of a on-skin sensorcontrol unit, according to the disclosure;

FIG. 15 is a top view of a base of the on-skin sensor control unit ofFIG. 14;

FIG. 16 is a bottom view of a cover of the on-skin sensor control unitof FIG. 14;

FIG. 17 is a perspective view of the on-skin sensor control unit of FIG.14 on the skin of a patient;

FIG. 18A is a block diagram of one embodiment of an on-skin sensorcontrol unit, according to the disclosure;

FIG. 18B is a block diagram of another embodiment of an on-skin sensorcontrol unit, according to the disclosure;

FIGS. 19A, 19B, 19C, and 19D are cross-sectional views of fourembodiments of conductive contacts disposed on an interior surface of ahousing of an on-skin sensor control unit, according to the disclosure;

FIGS. 19E and 19F are cross-sectional views of two embodiments ofconductive contacts disposed on an exterior surface of a housing of anon-skin sensor control unit, according to the disclosure;

FIGS. 20A and 20B are schematic diagrams of two embodiments of acurrent-to-voltage converter for use in an analyte monitoring device,according to the disclosure;

FIG. 21 is a block diagram of one embodiment of an open loop modulationsystem for use in an analyte monitoring device, according to thedisclosure;

FIG. 22 is a block diagram of one embodiment of a receiver/display unit,according to the disclosure;

FIG. 23 is a front view of one embodiment of a receiver/display unit;

FIG. 24 is a front view of a second embodiment of a receiver/displayunit;

FIG. 25 is a block diagram of one embodiment of a drug delivery system,according to the disclosure;

FIG. 26 is a perspective view of the internal structure of an insertiongun, according to the disclosure;

FIG. 27A is a top view of one embodiment of an on-skin sensor controlunit, according to the disclosure;

FIG. 27B is a top view of one embodiment of a mounting unit of theon-skin sensor control unit of FIG. 27A;

FIG. 28A is a top view of another embodiment of an on-skin sensorcontrol unit after insertion of an insertion device and a sensor,according to the disclosure;

FIG. 28B is a top view of one embodiment of a mounting unit of theon-skin sensor control unit of FIG. 28A;

FIG. 28C is a top view of one embodiment of a housing for at least aportion of the electronics of the on-skin sensor control unit of FIG.28A;

FIG. 28D is a bottom view of the housing of FIG. 28C;

FIG. 28E is a top view of the on-skin sensor control unit of FIG. 28Awith a cover of the housing removed;

FIG. 29 is a flowchart illustrating therapy related management routinein accordance with one embodiment; and

FIG. 30 is a flowchart illustrating therapy related management routinein accordance with one embodiment.

DETAILED DESCRIPTION

The present disclosure is applicable to an analyte monitoring systemusing an implantable sensor for the in vivo determination of aconcentration of an analyte, such as glucose or lactate, in a fluid. Thesensor can be, for example, subcutaneously implanted in a patient forthe continuous or periodic monitoring an analyte in a patient'sinterstitial fluid. This can then be used to infer the glucose level inthe patient's bloodstream. Other in vivo analyte sensors can be made,according to the disclosure, for insertion into a vein, artery, or otherportion of the body containing fluid. The analyte monitoring system istypically configured for monitoring the level of the analyte over a timeperiod which may range from days to weeks or longer.

The following definitions are provided for terms used herein:

A “counter electrode” refers to an electrode paired with the workingelectrode, through which passes a current equal in magnitude andopposite in sign to the current passing through the working electrode.In the context of the disclosure, the term “counter electrode” is meantto include counter electrodes which also function as referenceelectrodes (i.e., a counter/reference electrode).

An “electrochemical sensor” is a device configured to detect thepresence and/or measure the level of an analyte in a sample viaelectrochemical oxidation and reduction reactions on the sensor. Thesereactions are transduced to an electrical signal that can be correlatedto an amount, concentration, or level of an analyte in the sample.

“Electrolysis” is the electrooxidation or electroreduction of a compoundeither directly at an electrode or via one or more electron transferagents.

A compound is “immobilized” on a surface when it is entrapped on orchemically bound to the surface.

A “non-leachable” or “non-releasable” compound or a compound that is“non-leachably disposed” is meant to define a compound that is affixedon the sensor such that it does not substantially diffuse away from theworking surface of the working electrode for the period in which thesensor is used (e.g., the period in which the sensor is implanted in apatient or measuring a sample).

Components are “immobilized” within a sensor, for example, when thecomponents are covalently, ionically, or coordinatively bound toconstituents of the sensor and/or are entrapped in a polymeric orsol-gel matrix or membrane which precludes mobility.

An “electron transfer agent” is a compound that carries electronsbetween the analyte and the working electrode, either directly, or incooperation with other electron transfer agents. One example of anelectron transfer agent is a redox mediator.

A “working electrode” is an electrode at which the analyte (or a secondcompound whose level depends on the level of the analyte) iselectrooxidized or electroreduced with or without the agency of anelectron transfer agent.

A “working surface” is that portion of the working electrode which iscoated with or is accessible to the electron transfer agent andconfigured for exposure to an analyte-containing fluid.

A “sensing layer” is a component of the sensor which includesconstituents that facilitate the electrolysis of the analyte. Thesensing layer may include constituents such as an electron transferagent, a catalyst which catalyzes a reaction of the analyte to produce aresponse at the electrode, or both. In some embodiments of the sensor,the sensing layer is non-leachably disposed in proximity to or on theworking electrode.

A “non-corroding” conductive material includes non-metallic materials,such as carbon and conductive polymers.

Analyte Sensor Systems

The analyte monitoring systems of the present disclosure can be utilizedunder a variety of conditions. The particular configuration of a sensorand other units used in the analyte monitoring system may depend on theuse for which the analyte monitoring system is intended and theconditions under which the analyte monitoring system will operate. Oneembodiment of the analyte monitoring system includes a sensor configuredfor implantation into a patient or user. For example, implantation ofthe sensor may be made in the arterial or venous systems for directtesting of analyte levels in blood. Alternatively, a sensor may beimplanted in the interstitial tissue for determining the analyte levelin interstitial fluid. This level may be correlated and/or converted toanalyte levels in blood or other fluids. The site and depth ofimplantation may affect the particular shape, components, andconfiguration of the sensor. Subcutaneous implantation may be preferred,in some cases, to limit the depth of implantation of the sensor. Sensorsmay also be implanted in other regions of the body to determine analytelevels in other fluids. Examples of suitable sensor for use in theanalyte monitoring systems of the disclosure are described in U.S.patent application Ser. No. 09/034,372, incorporated herein byreference.

One embodiment of the analyte monitoring system 40 for use with animplantable sensor 42, and particularly for use with a subcutaneouslyimplantable sensor, is illustrated in block diagram form in FIG. 1. Theanalyte monitoring system 40 includes, at minimum, a sensor 42, aportion of which is configured for implantation (e.g., subcutaneous,venous, or arterial implantation) into a patient, and a sensor controlunit 44. The sensor 42 is coupled to the sensor control unit 44 which istypically attached to the skin of a patient. The sensor control unit 44operates the sensor 42, including, for example, providing a voltageacross the electrodes of the sensor 42 and collecting signals from thesensor 42. The sensor control unit 44 may evaluate the signals from thesensor 42 and/or transmit the signals to one or more optionalreceiver/display units 46, 48 for evaluation. The sensor control unit 44and/or the receiver/display units 46, 48 may display or otherwisecommunicate the current level of the analyte. Furthermore, the sensorcontrol unit 44 and/or the receiver/display units 46, 48 may indicate tothe patient, via, for example, an audible, visual, or othersensory-stimulating alarm, when the level of the analyte is at or near athreshold level. In some embodiments, a electrical shock can bedelivered to the patient as a warning through one of the electrodes orthe optional temperature probe of the sensor. For example, if glucose ismonitored then an alarm may be used to alert the patient to ahypoglycemic or hyperglycemic glucose level and/or to impendinghypoglycemia or hyperglycemia.

The Sensor

A sensor 42 includes at least one working electrode 58 formed on asubstrate 50, as shown in FIG. 2. The sensor 42 may also include atleast one counter electrode 60 (or counter/reference electrode) and/orat least one reference electrode 62 (see FIG. 8). The counter electrode60 and/or reference electrode 62 may be formed on the substrate 50 ormay be separate units. For example, the counter electrode and/orreference electrode may be formed on a second substrate which is alsoimplanted in the patient or, for some embodiments of the implantablesensors, the counter electrode and/or reference electrode may be placedon the skin of the patient with the working electrode or electrodesbeing implanted into the patient. The use of an on-the-skin counterand/or reference electrode with an implantable working electrode isdescribed in U.S. Pat. No. 5,593,852, incorporated herein by reference.

The working electrode or electrodes 58 are formed using conductivetraces 52 disposed on the substrate 50. The counter electrode 60 and/orreference electrode 62, as well as other optional portions of the sensor42, such as a temperature probe 66 (see FIG. 8), may also be formedusing conductive traces 52 disposed on the substrate 50. Theseconductive traces 52 may be formed over a smooth surface of thesubstrate 50 or within channels 54 formed by, for example, embossing,indenting or otherwise creating a depression in the substrate 50.

A sensing layer 64 (see FIGS. 3A and 3B) is often formed proximate to oron at least one of the working electrodes 58 to facilitate theelectrochemical detection of the analyte and the determination of itslevel in the sample fluid, particularly if the analyte can not beelectrolyzed at a desired rate and/or with a desired specificity on abare electrode. The sensing layer 64 may include an electron transferagent to transfer electrons directly or indirectly between the analyteand the working electrode 58. The sensing layer 64 may also contain acatalyst to catalyze a reaction of the analyte. The components of thesensing layer may be in a fluid or gel that is proximate to or incontact with the working electrode 58. Alternatively, the components ofthe sensing layer 64 may be disposed in a polymeric or sol-gel matrixthat is proximate to or on the working electrode 58. Preferably, thecomponents of the sensing layer 64 are non-leachably disposed within thesensor 42. More preferably, the components of the sensor 42 areimmobilized within the sensor 42.

In addition to the electrodes 58, 60, 62 and the sensing layer 64, thesensor 42 may also include a temperature probe 66 (see FIGS. 6 and 8), amass transport limiting layer 74 (see FIG. 9), a biocompatible layer 75(see FIG. 9), and/or other optional components, as described below. Eachof these items enhances the functioning of and/or results from thesensor 42, as discussed below.

The Substrate

The substrate 50 may be formed using a variety of non-conductingmaterials, including, for example, polymeric or plastic materials andceramic materials. Suitable materials for a particular sensor 42 may bedetermined, at least in part, based on the desired use of the sensor 42and properties of the materials.

In some embodiments, the substrate is flexible. For example, if thesensor 42 is configured for implantation into a patient, then the sensor42 may be made flexible (although rigid sensors may also be used forimplantable sensors) to reduce pain to the patient and damage to thetissue caused by the implantation of and/or the wearing of the sensor42. A flexible substrate 50 often increases the patient's comfort andallows a wider range of activities. Suitable materials for a flexiblesubstrate 50 include, for example, non-conducting plastic or polymericmaterials and other non-conducting, flexible, deformable materials.Examples of useful plastic or polymeric materials include thermoplasticssuch as polycarbonates, polyesters (e.g., Mylar™ and polyethyleneterephthalate (PET)), polyvinyl chloride (PVC), polyurethanes,polyethers, polyamides, polyimides, or copolymers of thesethermoplastics, such as PETG (glycol-modified polyethyleneterephthalate).

In other embodiments, the sensors 42 are made using a relatively rigidsubstrate 50 to, for example, provide structural support against bendingor breaking. Examples of rigid materials that may be used as thesubstrate 50 include poorly conducting ceramics, such as aluminum oxideand silicon dioxide. One advantage of an implantable sensor 42 having arigid substrate is that the sensor 42 may have a sharp point and/or asharp edge to aid in implantation of a sensor 42 without an additionalinsertion device.

It will be appreciated that for many sensors 42 and sensor applications,both rigid and flexible sensors will operate adequately. The flexibilityof the sensor 42 may also be controlled and varied along a continuum bychanging, for example, the composition and/or thickness of the substrate50.

In addition to considerations regarding flexibility, it is oftendesirable that implantable sensors 42 should have a substrate 50 whichis non-toxic. Preferably, the substrate 50 is approved by one or moreappropriate governmental agencies or private groups for in vivo use.

The sensor 42 may include optional features to facilitate insertion ofan implantable sensor 42, as shown in FIG. 12. For example, the sensor42 may be pointed at the tip 123 to ease insertion. In addition, thesensor 42 may include a barb 125 which assists in anchoring the sensor42 within the tissue of the patient during operation of the sensor 42.However, the barb 125 is typically small enough that little damage iscaused to the subcutaneous tissue when the sensor 42 is removed forreplacement.

Although the substrate 50 in at least some embodiments has uniformdimensions along the entire length of the sensor 42, in otherembodiments, the substrate 50 has a distal end 67 and a proximal end 65with different widths 53, 55, respectively, as illustrated in FIG. 2. Inthese embodiments, the distal end 67 of the substrate 50 may have arelatively narrow width 53. For sensors 42 which are implantable intothe subcutaneous tissue or another portion of a patient's body, thenarrow width 53 of the distal end 67 of the substrate 50 may facilitatethe implantation of the sensor 42. Often, the narrower the width of thesensor 42, the less pain the patient will feel during implantation ofthe sensor and afterwards.

For subcutaneously implantable sensors 42 which are designed forcontinuous or periodic monitoring of the analyte during normalactivities of the patient, a distal end 67 of the sensor 42 which is tobe implanted into the patient has a width 53 of 2 mm or less, preferably1 mm or less, and more preferably 0.5 mm or less. If the sensor 42 doesnot have regions of different widths, then the sensor 42 will typicallyhave an overall width of, for example, 2 mm, 1.5 mm, 1 mm, 0.5 mm, 0.25mm, or less. However, wider or narrower sensors may be used. Inparticular, wider implantable sensors may be used for insertion intoveins or arteries or when the movement of the patient is limited, forexample, when the patient is confined in bed or in a hospital.

Returning to FIG. 2, the proximal end 65 of the sensor 42 may have awidth 55 larger than the distal end 67 to facilitate the connectionbetween contact pads 49 of the electrodes and contacts on a controlunit. The wider the sensor 42 at this point, the larger the contact pads49 can be made. This may reduce the precision needed to properly connectthe sensor 42 to contacts on the control unit (e.g., sensor control unit44 of FIG. 1). However, the maximum width of the sensor 42 may beconstrained so that the sensor 42 remains small for the convenience andcomfort of the patient and/or to fit the desired size of the analytemonitor. For example, the proximal end 65 of a subcutaneouslyimplantable sensor 42, such as the sensor 42 illustrated in FIG. 1, mayhave a width 55 ranging from 0.5 mm to 15 mm, preferably from 1 mm to 10mm, and more preferably from 3 mm to 7 mm. However, wider or narrowersensors may be used in this and other in vivo applications.

The thickness of the substrate 50 may be determined by the mechanicalproperties of the substrate material (e.g., the strength, modulus,and/or flexibility of the material), the desired use of the sensor 42including stresses on the substrate 50 arising from that use, as well asthe depth of any channels or indentations formed in the substrate 50, asdiscussed below. Typically, the substrate 50 of a subcutaneouslyimplantable sensor 42 for continuous or periodic monitoring of the levelof an analyte while the patient engages in normal activities has athickness of 50 to 500 μm and preferably 100 to 300 μm. However, thickerand thinner substrates 50 may be used, particularly in other types of invivo sensors 42.

The length of the sensor 42 may have a wide range of values depending ona variety of factors. Factors which influence the length of animplantable sensor 42 may include the depth of implantation into thepatient and the ability of the patient to manipulate a small flexiblesensor 42 and make connections between the sensor 42 and the sensorcontrol unit 44. A subcutaneously implantable sensor 42 for the analytemonitor illustrated in FIG. 1 may have a length ranging from 0.3 to 5cm, however, longer or shorter sensors may be used. The length of thenarrow portion of the sensor 42 (e.g., the portion which issubcutaneously inserted into the patient), if the sensor 42 has narrowand wide portions, is typically about 0.25 to 2 cm in length. However,longer and shorter portions may be used. All or only a part of thisnarrow portion may be subcutaneously implanted into the patient. Thelengths of other implantable sensors 42 will vary depending, at least inpart, on the portion of the patient into which the sensor 42 is to beimplanted or inserted.

Conductive Traces

At least one conductive trace 52 is formed on the substrate for use inconstructing a working electrode 58. In addition, other conductivetraces 52 may be formed on the substrate 50 for use as electrodes (e.g.,additional working electrodes, as well as counter, counter/reference,and/or reference electrodes) and other components, such as a temperatureprobe. The conductive traces 52 may extend most of the distance along alength 57 of the sensor 50, as illustrated in FIG. 2, although this isnot necessary. The placement of the conductive traces 52 may depend onthe particular configuration of the analyte monitoring system (e.g., theplacement of control unit contacts and/or the sample chamber in relationto the sensor 42). For implantable sensors, particularly subcutaneouslyimplantable sensors, the conductive traces typically extend close to thetip of the sensor 42 to minimize the amount of the sensor that must beimplanted.

The conductive traces 52 may be formed on the substrate 50 by a varietyof techniques, including, for example, photolithography, screenprinting, or other impact or non-impact printing techniques. Theconductive traces 52 may also be formed by carbonizing conductive traces52 in an organic (e.g., polymeric or plastic) substrate 50 using alaser. A description of some exemplary methods for forming the sensor 42is provided in U.S. patent application Ser. No. 09/034,422, incorporatedherein by reference.

Another method for disposing the conductive traces 52 on the substrate50 includes the formation of recessed channels 54 in one or moresurfaces of the substrate 50 and the subsequent filling of theserecessed channels 54 with a conductive material 56, as shown in FIG. 3A.The recessed channels 54 may be formed by indenting, embossing, orotherwise creating a depression in the surface of the substrate 50.Exemplary methods for forming channels and electrodes in a surface of asubstrate can be found in U.S. patent application Ser. No. 09/034,422.The depth of the channels is typically related to the thickness of thesubstrate 50. In one embodiment, the channels have depths in the rangeof about 12.5 to 75 Tm (0.5 to 3 mils), and preferably about 25 to 50 Tm(1 to 2 mils).

The conductive traces are typically formed using a conductive material56 such as carbon (e.g., graphite), a conductive polymer, a metal oralloy (e.g., gold or gold alloy), or a metallic compound (e.g.,ruthenium dioxide or titanium dioxide). The formation of films ofcarbon, conductive polymer, metal, alloy, or metallic compound arewell-known and include, for example, chemical vapor deposition (CVD),physical vapor deposition, sputtering, reactive sputtering, printing,coating, and painting. The conductive material 56 which fills thechannels 54 is often formed using a precursor material, such as aconductive ink or paste. In these embodiments, the conductive material56 is deposited on the substrate 50 using methods such as coating,painting, or applying the material using a spreading instrument, such asa coating blade. Excess conductive material between the channels 54 isthen removed by, for example, running a blade along the substratesurface.

In one embodiment, the conductive material 56 is a part of a precursormaterial, such as a conductive ink, obtainable, for example, from Ercon,Inc. (Wareham, Mass.), Metech, Inc. (Elverson, Pa.), E.I. du Pont deNemours and Co. (Wilmington, Del.), Emca-Remex Products(Montgomeryville, Pa.), or MCA Services (Melbourn, Great Britain). Theconductive ink is typically applied as a semiliquid or paste whichcontains particles of the carbon, metal, alloy, or metallic compound anda solvent or dispersant. After application of the conductive ink on thesubstrate 50 (e.g., in the channels 54), the solvent or dispersantevaporates to leave behind a solid mass of conductive material 56.

In addition to the particles of carbon, metal, alloy, or metalliccompound, the conductive ink may also contain a binder. The binder mayoptionally be cured to further bind the conductive material 56 withinthe channel 54 and/or on the substrate 50. Curing the binder increasesthe conductivity of the conductive material 56. However, this istypically not necessary as the currents carried by the conductivematerial 56 within the conductive traces 52 are often relatively low(usually less than 1 μA and often less than 100 nA). Typical bindersinclude, for example, polyurethane resins, cellulose derivatives,elastomers, and highly fluorinated polymers. Examples of elastomersinclude silicones, polymeric dienes, and acrylonitrile-butadiene-styrene(ABS) resins. One example of a fluorinated polymer binder is Teflon®(DuPont, Wilmington, Del.). These binders are cured using, for example,heat or light, including ultraviolet (UV) light. The appropriate curingmethod typically depends on the particular binder which is used.

Often, when a liquid or semiliquid precursor of the conductive material56 (e.g., a conductive ink) is deposited in the channel 54, theprecursor fills the channel 54. However, when the solvent or dispersantevaporates, the conductive material 56 which remains may lose volumesuch that the conductive material 56 may or may not continue to fill thechannel 54. Preferred conductive materials 56 do not pull away from thesubstrate 50 as they lose volume, but rather decrease in height withinthe channel 54. These conductive materials 56 typically adhere well tothe substrate 50 and therefore do not pull away from the substrate 50during evaporation of the solvent or dispersant. Other suitableconductive materials 56 either adhere to at least a portion of thesubstrate 50 and/or contain another additive, such as a binder, whichadheres the conductive material 56 to the substrate 50. Preferably, theconductive material 56 in the channels 54 is non-leachable, and morepreferably immobilized on the substrate 50. In some embodiments, theconductive material 56 may be formed by multiple applications of aliquid or semiliquid precursor interspersed with removal of the solventor dispersant.

In another embodiment, the channels 54 are formed using a laser. Thelaser carbonizes the polymer or plastic material. The carbon formed inthis process is used as the conductive material 56. Additionalconductive material 56, such as a conductive carbon ink, may be used tosupplement the carbon formed by the laser.

In a further embodiment, the conductive traces 52 are formed by padprinting techniques. For example, a film of conductive material isformed either as a continuous film or as a coating layer deposited on acarrier film. This film of conductive material is brought between aprint head and the substrate 50. A pattern on the surface of thesubstrate 50 is made using the print head according to a desired patternof conductive traces 52. The conductive material is transferred bypressure and/or heat from the film of conductive material to thesubstrate 50. This technique often produces channels (e.g., depressionscaused by the print head) in the substrate 50. Alternatively, theconductive material is deposited on the surface of the substrate 50without forming substantial depressions.

In other embodiments, the conductive traces 52 are formed by non-impactprinting techniques. Such techniques include electrophotography andmagnetography. In these processes, an image of the conductive traces 52is electrically or magnetically formed on a drum. A laser or LED may beused to electrically form an image. A magnetic recording head may beused to magnetically form an image. A toner material (e.g., a conductivematerial, such as a conductive ink) is then attracted to portions of thedrum according to the image. The toner material is then applied to thesubstrate by contact between the drum and the substrate. For example,the substrate may be rolled over the drum. The toner material may thenbe dried and/or a binder in the toner material may be cured to adherethe toner material to the substrate.

Another non-impact printing technique includes ejecting droplets ofconductive material onto the substrate in a desired pattern. Examples ofthis technique include ink jet printing and piezo jet printing. An imageis sent to the printer which then ejects the conductive material (e.g.,a conductive ink) according to the pattern. The printer may provide acontinuous stream of conductive material or the printer may eject theconductive material in discrete amounts at the desired points.

Yet another non-impact printing embodiment of forming the conductivetraces includes an ionographic process. In the this process, a curable,liquid precursor, such as a photopolymerizable acrylic resin (e.g.,Solimer 7501 from Cubital, Bad Kreuznach, Germany) is deposited over asurface of a substrate 50. A photomask having a positive or negativeimage of the conductive traces 52 is then used to cure the liquidprecursor. Light (e.g., visible or ultraviolet light) is directedthrough the photomask to cure the liquid precursor and form a solidlayer over the substrate according to the image on the photomask.Uncured liquid precursor is removed leaving behind channels 54 in thesolid layer. These channels 54 can then be filled with conductivematerial 56 to form conductive traces 52.

Conductive traces 52 (and channels 54, if used) can be formed withrelatively narrow widths, for example, in the range of 25 to 250 μm, andincluding widths of, for example, 250 μm, 150 μm, 100 μm, 75 μm, 50 μm,25 μm or less by the methods described above. In embodiments with two ormore conductive traces 52 on the same side of the substrate 50, theconductive traces 52 are separated by distances sufficient to preventconduction between the conductive traces 52. The edge-to-edge distancebetween the conductive traces is preferably in the range of 25 to 250 μmand may be, for example, 150 μm, 100 μm, 75 μm, 50 μm, or less. Thedensity of the conductive traces 52 on the substrate 50 is preferably inthe range of about 150 to 700 μm/trace and may be as small as 667μm/trace or less, 333 μm/trace or less, or even 167 μm/trace or less.

The working electrode 58 and the counter electrode 60 (if a separatereference electrode is used) are often made using a conductive material56, such as carbon. Suitable carbon conductive inks are available fromErcon, Inc. (Wareham, Mass.), Metech, Inc. (Elverson, Pa.), E.I. du Pontde Nemours and Co. (Wilmington, Del.), Emca-Remex Products(Montgomeryville, Pa.), or MCA Services (Melbourn, Great Britain).Typically, the working surface 51 of the working electrode 58 is atleast a portion of the conductive trace 52 that is in contact with theanalyte-containing fluid (e.g., implanted in the patient).

The reference electrode 62 and/or counter/reference electrode aretypically formed using conductive material 56 that is a suitablereference material, for example silver/silver chloride or anon-leachable redox couple bound to a conductive material, for example,a carbon-bound redox couple. Suitable silver/silver chloride conductiveinks are available from Ercon, Inc. (Wareham, Mass.), Metech, Inc.(Elverson, Pa.), E.I. du Pont de Nemours and Co. (Wilmington, Del.),Emca-Remex Products (Montgomeryville, Pa.), or MCA Services (Melbourn,Great Britain). Silver/silver chloride electrodes illustrate a type ofreference electrode that involves the reaction of a metal electrode witha constituent of the sample or body fluid, in this case, Cl.

Suitable redox couples for binding to the conductive material of thereference electrode include, for example, redox polymers (e.g., polymershaving multiple redox centers.) It is preferred that the referenceelectrode surface be non-corroding so that an erroneous potential is notmeasured. Preferred conductive materials include less corrosive metals,such as gold and palladium. Most preferred are non-corrosive materialsincluding non-metallic conductors, such as carbon and conductingpolymers. A redox polymer can be adsorbed on or covalently bound to theconductive material of the reference electrode, such as a carbon surfaceof a conductive trace 52. Non-polymeric redox couples can be similarlybound to carbon or gold surfaces.

A variety of methods may be used to immobilize a redox polymer on anelectrode surface. One method is adsorptive immobilization. This methodis particularly useful for redox polymers with relatively high molecularweights. The molecular weight of a polymer may be increased, forexample, by cross-linking.

Another method for immobilizing the redox polymer includes thefunctionalization of the electrode surface and then the chemicalbonding, often covalently, of the redox polymer to the functional groupson the electrode surface. One example of this type of immobilizationbegins with a poly(4-vinylpyridine). The polymer's pyridine rings are,in part, complexed with a reducible/oxidizable species, such as[Os(bpy)₂Cl]^(+/2+) where bpy is 2,2′-bipyridine. Part of the pyridinerings are quaternized by reaction with 2-bromoethylamine. The polymer isthen crosslinked, for example, using a diepoxide, such as polyethyleneglycol diglycidyl ether.

Carbon surfaces can be modified for attachment of a redox species orpolymer, for example, by electroreduction of a diazonium salt. As anillustration, reduction of a diazonium salt formed upon diazotization ofp-aminobenzoic acid modifies a carbon surface with phenylcarboxylic acidfunctional groups. These functional groups can then be activated by acarbodiimide, such as 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimidehydrochloride. The activated functional groups are then bound with aamine-functionalized redox couple, such as the quaternizedosmium-containing redox polymer described above or2-aminoethylferrocene, to form the redox couple.

Similarly, gold can be functionalized by an amine, such as cystamine. Aredox couple such as [Os(bpy)₂(pyridine-4-carboxylate)Cl]^(0/+) isactivated by 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimidehydrochloride to form a reactive O-acylisourea which reacts with thegold-bound amine to form an amide.

In one embodiment, in addition to using the conductive traces 52 aselectrodes or probe leads, two or more of the conductive traces 52 onthe substrate 50 are used to give the patient a mild electrical shockwhen, for example, the analyte level exceeds a threshold level. Thisshock may act as a warning or alarm to the patient to initiate someaction to restore the appropriate level of the analyte.

The mild electrical shock is produced by applying a potential betweenany two conductive traces 52 that are not otherwise connected by aconductive path. For example, two of the electrodes 58, 60, 62 or oneelectrode 58, 60, 62 and the temperature probe 66 may be used to providethe mild shock. Preferably, the working electrode 58 and the referenceelectrode 62 are not used for this purpose as this may cause some damageto the chemical components on or proximate to the particular electrode(e.g., the sensing layer on the working electrode or the redox couple onthe reference electrode).

The current used to produce the mild shock is typically 0.1 to 1 mA.Higher or lower currents may be used, although care should be taken toavoid harm to the patient. The potential between the conductive tracesis typically 1 to 10 volts. However, higher or lower voltages may beused depending, for example, on the resistance of the conductive traces52, the distance between the conductive traces 52 and the desired amountof current. When the mild shock is delivered, potentials at the workingelectrode 58 and across the temperature probe 66 may be removed toprevent harm to those components caused by unwanted conduction betweenthe working electrode 58 (and/or temperature probe 66, if used) and theconductive traces 52 which provide the mild shock.

Contact Pads

Typically, each of the conductive traces 52 includes a contact pad 49.The contact pad 49 may simply be a portion of the conductive trace 52that is indistinguishable from the rest of the trace 52 except that thecontact pad 49 is brought into contact with the conductive contacts of acontrol unit (e.g., the sensor control unit 44 of FIG. 1). Morecommonly, however, the contact pad 49 is a region of the conductivetrace 52 that has a larger width than other regions of the trace 52 tofacilitate a connection with the contacts on the control unit. By makingthe contact pads 49 relatively large as compared with the width of theconductive traces 52, the need for precise registration between thecontact pads 49 and the contacts on the control unit is less criticalthan with small contact pads.

The contact pads 49 are typically made using the same material as theconductive material 56 of the conductive traces 52. However, this is notnecessary. Although metal, alloys, and metallic compounds may be used toform the contact pads 49, in some embodiments, it is desirable to makethe contact pads 49 from a carbon or other non-metallic material, suchas a conducting polymer. In contrast to metal or alloy contact pads,carbon and other non-metallic contact pads are not easily corroded ifthe contact pads 49 are in a wet, moist, or humid environment. Metalsand alloys may corrode under these conditions, particularly if thecontact pads 49 and contacts of the control unit are made usingdifferent metals or alloys. However, carbon and non-metallic contactpads 49 do not significantly corrode, even if the contacts of thecontrol device are metal or alloy.

One embodiment of the disclosure includes a sensor 42 having contactpads 49 and a control unit 44 having conductive contacts (not shown).During operation of the sensor 42, the contact pads 49 and conductivecontacts are in contact with each other. In this embodiment, either thecontact pads 49 or the conductive contacts are made using anon-corroding, conductive material. Such materials include, for example,carbon and conducting polymers. Preferred non-corroding materialsinclude graphite and vitreous carbon. The opposing contact pad orconductive contact is made using carbon, a conducting polymer, a metal,such as gold, palladium, or platinum group metal, or a metalliccompound, such as ruthenium dioxide. This configuration of contact padsand conductive contacts typically reduces corrosion. Preferably, whenthe sensor is placed in a 3 mM, and more preferably, in a 100 mM, NaClsolution, the signal arising due to the corrosion of the contact padsand/or conductive contacts is less than 3% of the signal generated bythe sensor when exposed to concentration of analyte in the normalphysiological range. For at least some subcutaneous glucose sensors, thecurrent generated by analyte in a normal physiological range ranges from3 to 500 nA.

Each of the electrodes 58, 60, 62, as well as the two probe leads 68, 70of the temperature probe 66 (described below), are connected to contactpads 49 as shown in FIGS. 10 and 11. In one embodiment (not shown), thecontact pads 49 are on the same side of the substrate 50 as therespective electrodes or temperature probe leads to which the contactpads 49 are attached.

In other embodiments, the conductive traces 52 on at least one side areconnected through vias in the substrate to contact pads 49 a on theopposite surface of the substrate 50, as shown in FIGS. 10 and 11. Anadvantage of this configuration is that contact between the contacts onthe control unit and each of the electrodes 58, 60, 62 and the probeleads 68,70 of the temperature probe 66 can be made from a single sideof the substrate 50.

In yet other embodiments (not shown), vias through the substrate areused to provide contact pads on both sides of the substrate 50 for eachconductive trace 52. The vias connecting the conductive traces 52 withthe contact pads 49 a can be formed by making holes through thesubstrate 50 at the appropriate points and then filling the holes withconductive material 56.

Exemplary Electrode Configurations

A number of exemplary electrode configurations are described below,however, it will be understood that other configurations may also beused. In one embodiment, illustrated in FIG. 3A, the sensor 42 includestwo working electrodes 58 a, 58 b and one counter electrode 60, whichalso functions as a reference electrode. In another embodiment, thesensor includes one working electrode 58 a, one counter electrode 60,and one reference electrode 62, as shown in FIG. 3B. Each of theseembodiments is illustrated with all of the electrodes formed on the sameside of the substrate 50.

Alternatively, one or more of the electrodes may be formed on anopposing side of the substrate 50. This may be convenient if theelectrodes are formed using two different types of conductive material56 (e.g., carbon and silver/silver chloride). Then, at least in someembodiments, only one type of conductive material 56 needs to be appliedto each side of the substrate 50, thereby reducing the number of stepsin the manufacturing process and/or easing the registration constraintsin the process. For example, if the working electrode 58 is formed usinga carbon-based conductive material 56 and the reference orcounter/reference electrode is formed using a silver/silver chlorideconductive material 56, then the working electrode and reference orcounter/reference electrode may be formed on opposing sides of thesubstrate 50 for ease of manufacture.

In another embodiment, two working electrodes 58 and one counterelectrode 60 are formed on one side of the substrate 50 and onereference electrode 62 and a temperature probe 66 are formed on anopposing side of the substrate 50, as illustrated in FIG. 6. Theopposing sides of the tip of this embodiment of the sensor 42 areillustrated in FIGS. 7 and 8.

Sensing Layer

Some analytes, such as oxygen, can be directly electrooxidized orelectroreduced on the working electrode 58. Other analytes, such asglucose and lactate, require the presence of at least one electrontransfer agent and/or at least one catalyst to facilitate theelectrooxidation or electroreduction of the analyte. Catalysts may alsobe used for those analyte, such as oxygen, that can be directlyelectrooxidized or electroreduced on the working electrode 58. For theseanalytes, each working electrode 58 has a sensing layer 64 formedproximate to or on a working surface of the working electrode 58.Typically, the sensing layer 64 is formed near or on only a smallportion of the working electrode 58, often near a tip of the sensor 42.This limits the amount of material needed to form the sensor 42 andplaces the sensing layer 64 in the best position for contact with theanalyte-containing fluid (e.g., a body fluid, sample fluid, or carrierfluid).

The sensing layer 64 includes one or more components designed tofacilitate the electrolysis of the analyte. The sensing layer 64 mayinclude, for example, a catalyst to catalyze a reaction of the analyteand produce a response at the working electrode 58, an electron transferagent to indirectly or directly transfer electrons between the analyteand the working electrode 58, or both.

The sensing layer 64 may be formed as a solid composition of the desiredcomponents (e.g., an electron transfer agent and/or a catalyst). Thesecomponents are preferably non-leachable from the sensor 42 and morepreferably are immobilized on the sensor 42. For example, the componentsmay be immobilized on a working electrode 58. Alternatively, thecomponents of the sensing layer 64 may be immobilized within or betweenone or more membranes or films disposed over the working electrode 58 orthe components may be immobilized in a polymeric or sol-gel matrix.Examples of immobilized sensing layers are described in U.S. Pat. Nos.5,262,035, 5,264,104, 5,264,105, 5,320,725, 5,593,852, and 5,665,222,U.S. patent application Ser. No. 08/540,789, and PCT Patent ApplicationNo. US98/02403 entitled “Soybean Peroxidase Electrochemical Sensor”,filed on Feb. 11, 1998, incorporated herein by reference.

In some embodiments, one or more of the components of the sensing layer64 may be solvated, dispersed, or suspended in a fluid within thesensing layer 64, instead of forming a solid composition. The fluid maybe provided with the sensor 42 or may be absorbed by the sensor 42 fromthe analyte-containing fluid. Preferably, the components which aresolvated, dispersed, or suspended in this type of sensing layer 64 arenon-leachable from the sensing layer. Non-leachability may beaccomplished, for example, by providing barriers (e.g., the electrode,substrate, membranes, and/or films) around the sensing layer whichprevent the leaching of the components of the sensing layer 64. Oneexample of such a barrier is a microporous membrane or film which allowsdiffusion of the analyte into the sensing layer 64 to make contact withthe components of the sensing layer 64, but reduces or eliminates thediffusion of the sensing layer components (e.g., a electron transferagent and/or a catalyst) out of the sensing layer 64.

A variety of different sensing layer configurations can be used. In oneembodiment, the sensing layer 64 is deposited on the conductive material56 of a working electrode 58 a, as illustrated in FIGS. 3A and 3B. Thesensing layer 64 may extend beyond the conductive material 56 of theworking electrode 58 a. In some cases, the sensing layer 64 may alsoextend over the counter electrode 60 or reference electrode 62 withoutdegrading the performance of the glucose sensor. For those sensors 42which utilize channels 54 within which the conductive material 56 isdeposited, a portion of the sensing layer 64 may be formed within thechannel 54 if the conductive material 56 does not fill the channel 54.

A sensing layer 64 in direct contact with the working electrode 58 a maycontain an electron transfer agent to transfer electrons directly orindirectly between the analyte and the working electrode, as well as acatalyst to facilitate a reaction of the analyte. For example, aglucose, lactate, or oxygen electrode may be formed having a sensinglayer which contains a catalyst, such as glucose oxidase, lactateoxidase, or laccase, respectively, and an electron transfer agent thatfacilitates the electrooxidation of the glucose, lactate, or oxygen,respectively.

In another embodiment, the sensing layer 64 is not deposited directly onthe working electrode 58 a. Instead, the sensing layer 64 is spacedapart from the working electrode 58 a, as illustrated in FIG. 4A, andseparated from the working electrode 58 a by a separation layer 61. Theseparation layer 61 typically includes one or more membranes or films.In addition to separating the working electrode 58 a from the sensinglayer 64, the separation layer 61 may also act as a mass transportlimiting layer or an interferent eliminating layer, as described below.

Typically, a sensing layer 64, which is not in direct contact with theworking electrode 58 a, includes a catalyst that facilitates a reactionof the analyte. However, this sensing layer 64 typically does notinclude an electron transfer agent that transfers electrons directlyfrom the working electrode 58 a to the analyte, as the sensing layer 64is spaced apart from the working electrode 58 a. One example of thistype of sensor is a glucose or lactate sensor which includes an enzyme(e.g., glucose oxidase or lactate oxidase, respectively) in the sensinglayer 64. The glucose or lactate reacts with a second compound (e.g.,oxygen) in the presence of the enzyme. The second compound is thenelectrooxidized or electroreduced at the electrode. Changes in thesignal at the electrode indicate changes in the level of the secondcompound in the fluid and are proportional to changes in glucose orlactate level and, thus, correlate to the analyte level.

In another embodiment, two sensing layers 63, 64 are used, as shown inFIG. 4B. Each of the two sensing layers 63, 64 may be independentlyformed on the working electrode 58 a or in proximity to the workingelectrode 58 a. One sensing layer 64 is typically, although notnecessarily, spaced apart from the working electrode 58 a. For example,this sensing layer 64 may include a catalyst which catalyzes a reactionof the analyte to form a product compound. The product compound is thenelectrolyzed in the second sensing layer 63 which may include anelectron transfer agent to transfer electrons between the workingelectrode 58 a and the product compound and/or a second catalyst tocatalyze a reaction of the product compound to generate a signal at theworking electrode 58 a.

For example, a glucose or lactate sensor may include a first sensinglayer 64 which is spaced apart from the working electrode and containsan enzyme, for example, glucose oxidase or lactate oxidase. The reactionof glucose or lactate in the presence of the appropriate enzyme formshydrogen peroxide. A second sensing layer 63 is provided directly on theworking electrode 58 a and contains a peroxidase enzyme and an electrontransfer agent to generate a signal at the electrode in response to thehydrogen peroxide. The level of hydrogen peroxide indicated by thesensor then correlates to the level of glucose or lactate. Anothersensor which operates similarly can be made using a single sensing layerwith both the glucose or lactate oxidase and the peroxidase beingdeposited in the single sensing layer. Examples of such sensors aredescribed in U.S. Pat. No. 5,593,852, U.S. patent application Ser. No.08/540,789, and PCT Patent Application No. US98/02403 entitled “SoybeanPeroxidase Electrochemical Sensor”, filed on Feb. 11, 1998, incorporatedherein by reference.

In some embodiments, one or more of the working electrodes 58 b do nothave a corresponding sensing layer 64, as shown in FIGS. 3A and 4A, orhave a sensing layer (not shown) which does not contain one or morecomponents (e.g., an electron transfer agent or catalyst) needed toelectrolyze the analyte. The signal generated at this working electrode58 b typically arises from interferents and other sources, such as ions,in the fluid, and not in response to the analyte (because the analyte isnot electrooxidized or electroreduced). Thus, the signal at this workingelectrode 58 b corresponds to a background signal. The background signalcan be removed from the analyte signal obtained from other workingelectrodes 58 a that are associated with fully-functional sensing layers64 by, for example, subtracting the signal at working electrode 58 bfrom the signal at working electrode 58 a.

Sensors having multiple working electrodes 58 a may also be used toobtain more precise results by averaging the signals or measurementsgenerated at these working electrodes 58 a. In addition, multiplereadings at a single working electrode 58 a or at multiple workingelectrodes may be averaged to obtain more precise data.

Electron Transfer Agent

In many embodiments, the sensing layer 64 contains one or more electrontransfer agents in contact with the conductive material 56 of theworking electrode 58, as shown in FIGS. 3A and 3B. In some embodimentsof the disclosure, there is little or no leaching of the electrontransfer agent away from the working electrode 58 during the period inwhich the sensor 42 is implanted in the patient. A diffusing orleachable (i.e., releasable) electron transfer agent often diffuses intothe analyte-containing fluid, thereby reducing the effectiveness of theelectrode by reducing the sensitivity of the sensor over time. Inaddition, a diffusing or leaching electron transfer agent in animplantable sensor 42 may also cause damage to the patient. In theseembodiments, preferably, at least 90%, more preferably, at least 95%,and, most preferably, at least 99%, of the electron transfer agentremains disposed on the sensor after immersion in the analyte-containingfluid for 24 hours, and, more preferably, for 72 hours. In particular,for an implantable sensor, preferably, at least 90%, more preferably, atleast 95%, and most preferably, at least 99%, of the electron transferagent remains disposed on the sensor after immersion in the body fluidat 37° C. for 24 hours, and, more preferably, for 72 hours.

In some embodiments of the disclosure, to prevent leaching, the electrontransfer agents are bound or otherwise immobilized on the workingelectrode 58 or between or within one or more membranes or filmsdisposed over the working electrode 58. The electron transfer agent maybe immobilized on the working electrode 58 using, for example, apolymeric or sol-gel immobilization technique. Alternatively, theelectron transfer agent may be chemically (e.g., ionically, covalently,or coordinatively) bound to the working electrode 58, either directly orindirectly through another molecule, such as a polymer, that is in turnbound to the working electrode 58.

Application of the sensing layer 64 on a working electrode 58 a is onemethod for creating a working surface for the working electrode 58 a, asshown in FIGS. 3A and 3B. The electron transfer agent mediates thetransfer of electrons to electrooxidize or electroreduce an analyte andthereby permits a current flow between the working electrode 58 and thecounter electrode 60 via the analyte. The mediation of the electrontransfer agent facilitates the electrochemical analysis of analyteswhich are not suited for direct electrochemical reaction on anelectrode.

In general, the preferred electron transfer agents are electroreducibleand electrooxidizable ions or molecules having redox potentials that area few hundred millivolts above or below the redox potential of thestandard calomel electrode (SCE). Preferably, the electron transferagents are not more reducing than about −150 mV and not more oxidizingthan about +400 mV versus SCE.

The electron transfer agent may be organic, organometallic, orinorganic. Examples of organic redox species are quinones and speciesthat in their oxidized state have quinoid structures, such as Nile blueand indophenol. Some quinones and partially oxidized quinhydrones reactwith functional groups of proteins such as the thiol groups of cysteine,the amine groups of lysine and arginine, and the phenolic groups oftyrosine which may render those redox species unsuitable for some of thesensors of the present disclosure because of the presence of theinterfering proteins in an analyte-containing fluid. Usually substitutedquinones and molecules with quinoid structure are less reactive withproteins and are preferred. A preferred tetrasubstituted quinone usuallyhas carbon atoms in positions 1, 2, 3, and 4.

In general, electron transfer agents suitable for use in the disclosurehave structures or charges which prevent or substantially reduce thediffusional loss of the electron transfer agent during the period oftime that the sample is being analyzed. The preferred electron transferagents include a redox species bound to a polymer which can in turn beimmobilized on the working electrode. The bond between the redox speciesand the polymer may be covalent, coordinative, or ionic. Useful electrontransfer agents and methods for producing them are described in U.S.Pat. Nos. 5,264,104; 5,356,786; 5,262,035; and 5,320,725, incorporatedherein by reference. Although any organic or organometallic redoxspecies can be bound to a polymer and used as an electron transferagent, the preferred redox species is a transition metal compound orcomplex. The preferred transition metal compounds or complexes includeosmium, ruthenium, iron, and cobalt compounds or complexes. The mostpreferred are osmium compounds and complexes. It will be recognized thatmany of the redox species described below may also be used, typicallywithout a polymeric component, as electron transfer agents in a carrierfluid or in a sensing layer of a sensor where leaching of the electrontransfer agent is acceptable.

One type of non-releasable polymeric electron transfer agent contains aredox species covalently bound in a polymeric composition. An example ofthis type of mediator is poly(vinylferrocene).

Another type of non-releasable electron transfer agent contains anionically-bound redox species. Typically, this type of mediator includesa charged polymer coupled to an oppositely charged redox species.Examples of this type of mediator include a negatively charged polymersuch as Nafion® (DuPont) coupled to a positively charged redox speciessuch as an osmium or ruthenium polypyridyl cation. Another example of anionically-bound mediator is a positively charged polymer such asquaternized poly(4-vinyl pyridine) or poly(1-vinyl imidazole) coupled toa negatively charged redox species such as ferricyanide or ferrocyanide.The preferred ionically-bound redox species is a highly charged redoxspecies bound within an oppositely charged redox polymer.

In another embodiment of the disclosure, suitable non-releasableelectron transfer agents include a redox species coordinatively bound toa polymer. For example, the mediator may be formed by coordination of anosmium or cobalt 2, 2′-bipyridyl complex to poly(1-vinyl imidazole) orpoly(4-vinyl pyridine).

The preferred electron transfer agents are osmium transition metalcomplexes with one or more ligands, each ligand having anitrogen-containing heterocycle such as 2,2′-bipyridine,1,10-phenanthroline, or derivatives thereof. Furthermore, the preferredelectron transfer agents also have one or more ligands covalently boundin a polymer, each ligand having at least one nitrogen-containingheterocycle, such as pyridine, imidazole, or derivatives thereof. Thesepreferred electron transfer agents exchange electrons rapidly betweeneach other and the working electrodes 58 so that the complex can berapidly oxidized and reduced.

One example of a particularly useful electron transfer agent includes(a) a polymer or copolymer having pyridine or imidazole functionalgroups and (b) osmium cations complexed with two ligands, each ligandcontaining 2,2′-bipyridine, 1,10-phenanthroline, or derivatives thereof,the two ligands not necessarily being the same. Preferred derivatives of2,2′-bipyridine for complexation with the osmium cation are4,4′-dimethyl-2,2′-bipyridine and mono-, di-, andpolyalkoxy-2,2′-bipyridines, such as 4,4′-dimethoxy-2,2′-bipyridine.Preferred derivatives of 1,10-phenanthroline for complexation with theosmium cation are 4,7-dimethyl-1,10-phenanthroline and mono, di-, andpolyalkoxy-1,10-phenanthrolines, such as4,7-dimethoxy-1,10-phenanthroline. Preferred polymers for complexationwith the osmium cation include polymers and copolymers of poly(1-vinylimidazole) (referred to as “PVI”) and poly(4-vinyl pyridine) (referredto as “PVP”). Suitable copolymer substituents of poly(1-vinyl imidazole)include acrylonitrile, acrylamide, and substituted or quaternizedN-vinyl imidazole. Most preferred are electron transfer agents withosmium complexed to a polymer or copolymer of poly(1-vinyl imidazole).

The preferred electron transfer agents have a redox potential rangingfrom −100 mV to about +150 mV versus the standard calomel electrode(SCE). Preferably, the potential of the electron transfer agent rangesfrom −100 mV to +150 mV and more preferably, the potential ranges from−50 mV to +50 mV. The most preferred electron transfer agents haveosmium redox centers and a redox potential ranging from +50 mV to −150mV versus SCE.

Catalyst

The sensing layer 64 may also include a catalyst which is capable ofcatalyzing a reaction of the analyte. The catalyst may also, in someembodiments, act as an electron transfer agent. One example of asuitable catalyst is an enzyme which catalyzes a reaction of theanalyte. For example, a catalyst, such as a glucose oxidase, glucosedehydrogenase (e.g., pyrroloquinoline quinone glucose dehydrogenase(PQQ)), or oligosaccharide dehydrogenase, may be used when the analyteis glucose. A lactate oxidase or lactate dehydrogenase may be used whenthe analyte is lactate. Laccase may be used when the analyte is oxygenor when oxygen is generated or consumed in response to a reaction of theanalyte.

Preferably, the catalyst is non-leachably disposed on the sensor,whether the catalyst is part of a solid sensing layer in the sensor orsolvated in a fluid within the sensing layer. More preferably, thecatalyst is immobilized within the sensor (e.g., on the electrode and/orwithin or between a membrane or film) to prevent unwanted leaching ofthe catalyst away from the working electrode 58 and into the patient.This may be accomplished, for example, by attaching the catalyst to apolymer, cross linking the catalyst with another electron transfer agent(which, as described above, can be polymeric), and/or providing one ormore barrier membranes or films with pore sizes smaller than thecatalyst.

As described above, a second catalyst may also be used. This secondcatalyst is often used to catalyze a reaction of a product compoundresulting from the catalyzed reaction of the analyte. The secondcatalyst typically operates with an electron transfer agent toelectrolyze the product compound to generate a signal at the workingelectrode. Alternatively, the second catalyst may be provided in aninterferent-eliminating layer to catalyze reactions that removeinterferents, as described below.

One embodiment of the disclosure is an electrochemical sensor in whichthe catalyst is mixed or dispersed in the conductive material 56 whichforms the conductive trace 52 of a working electrode 58. This may beaccomplished, for example, by mixing a catalyst, such as an enzyme, in acarbon ink and applying the mixture into a channel 54 on the surface ofthe substrate 50. Preferably, the catalyst is immobilized in the channel53 so that it can not leach away from the working electrode 58. This maybe accomplished, for example, by curing a binder in the carbon ink usinga curing technique appropriate to the binder. Curing techniques include,for example, evaporation of a solvent or dispersant, exposure toultraviolet light, or exposure to heat. Typically, the mixture isapplied under conditions that do not substantially degrade the catalyst.For example, the catalyst may be an enzyme that is heat-sensitive. Theenzyme and conductive material mixture should be applied and cured,preferably, without sustained periods of heating. The mixture may becured using evaporation or UV curing techniques or by the exposure toheat that is sufficiently short that the catalyst is not substantiallydegraded.

Another consideration for in vivo analyte sensors is the thermostabilityof the catalyst. Many enzymes have only limited stability at biologicaltemperatures. Thus, it may be necessary to use large amounts of thecatalyst and/or use a catalyst that is thermostable at the necessarytemperature (e.g., 37° C. or higher for normal body temperature). Athermostable catalyst may be defined as a catalyst which loses less than5% of its activity when held at 37° C. for at least one hour,preferably, at least one day, and more preferably at least three days.One example of a thermostable catalyst is soybean peroxidase. Thisparticular thermostable catalyst may be used in a glucose or lactatesensor when combined either in the same or separate sensing layers withglucose or lactate oxidase or dehydrogenase. A further description ofthermostable catalysts and their use in electrochemical disclosures isfound in U.S. Pat. No. 5,665,222 U.S. patent application Ser. No.08/540,789, and PCT Application No. US98/02403 entitled “SoybeanPeroxidase Electrochemical Sensor”, filed on Feb. 11, 1998, AttorneyDocket No. M&G 12008.8WOI2.

Electrolysis of the Analyte

To electrolyze the analyte, a potential (versus a reference potential)is applied across the working and counter electrodes 58, 60. The minimummagnitude of the applied potential is often dependent on the particularelectron transfer agent, analyte (if the analyte is directlyelectrolyzed at the electrode), or second compound (if a secondcompound, such as oxygen or hydrogen peroxide, whose level is dependenton the analyte level, is directly electrolyzed at the electrode). Theapplied potential usually equals or is more oxidizing or reducing,depending on the desired electrochemical reaction, than the redoxpotential of the electron transfer agent, analyte, or second compound,whichever is directly electrolyzed at the electrode. The potential atthe working electrode is typically large enough to drive theelectrochemical reaction to or near completion.

The magnitude of the potential may optionally be limited to preventsignificant (as determined by the current generated in response to theanalyte) electrochemical reaction of interferents, such as urate,ascorbate, and acetaminophen. The limitation of the potential may beobviated if these interferents have been removed in another way, such asby providing an interferent-limiting barrier, as described below, or byincluding a working electrode 58 b (see FIG. 3A) from which a backgroundsignal may be obtained.

When a potential is applied between the working electrode 58 and thecounter electrode 60, an electrical current will flow. The current is aresult of the electrolysis of the analyte or a second compound whoselevel is affected by the analyte. In one embodiment, the electrochemicalreaction occurs via an electron transfer agent and the optionalcatalyst. Many analytes B are oxidized (or reduced) to products C by anelectron transfer agent species A in the presence of an appropriatecatalyst (e.g., an enzyme). The electron transfer agent A is thenoxidized (or reduced) at the electrode. Electrons are collected by (orremoved from) the electrode and the resulting current is measured. Thisprocess is illustrated by reaction equations (1) and (2) (similarequations may be written for the reduction of the analyte B by a redoxmediator A in the presence of a catalyst):

$\begin{matrix}{{{{nA}({ox})} + B}\overset{catalyst}{arrow}{{{nA}({red})} + C}} & (1) \\{{{nA}({red})}\overset{electrode}{arrow}{{{nA}({ox})} + {ne}^{-}}} & (2)\end{matrix}$

As an example, an electrochemical sensor may be based on the reaction ofa glucose molecule with two non-leachable ferricyanide anions in thepresence of glucose oxidase to produce two non-leachable ferrocyanideanions, two hydrogen ions, and gluconolactone. The amount of glucosepresent is assayed by electrooxidizing the non-leachable ferrocyanideanions to non-leachable ferricyanide anions and measuring the current.

In another embodiment, a second compound whose level is affected by theanalyte is electrolyzed at the working electrode. In some cases, theanalyte D and the second compound, in this case, a reactant compound E,such as oxygen, react in the presence of the catalyst, as shown inreaction equation (3).

$\begin{matrix}{{D + E}\overset{catalyst}{arrow}{F + G}} & (3)\end{matrix}$

The reactant compound E is then directly oxidized (or reduced) at theworking electrode, as shown in reaction equation (4)

$\begin{matrix}{{{nE}({red})}\overset{electrode}{arrow}{{{nE}( {ox} )} + {ne}^{-}}} & (4)\end{matrix}$

Alternatively, the reactant compound E is indirectly oxidized (orreduced) using an electron transfer agent H (optionally in the presenceof a catalyst), that is subsequently reduced or oxidized at theelectrode, as shown in reaction equations (5) and (6).

$\begin{matrix} {{n{H( {ox} )}} + E}arrow{{n{H( {red} )}} + I}  & (5) \\{{{nH}( {r{ed}} )}\overset{electrode}{arrow}{{{nH}( {ox} )} + {ne}^{-}}} & (6)\end{matrix}$

In either case, changes in the concentration of the reactant compound,as indicated by the signal at the working electrode, correspondinversely to changes in the analyte (i.e., as the level of analyteincrease then the level of reactant compound and the signal at theelectrode decreases.)

In other embodiments, the relevant second compound is a product compoundF, as shown in reaction equation (3). The product compound F is formedby the catalyzed reaction of analyte D and then be directly electrolyzedat the electrode or indirectly electrolyzed using an electron transferagent and, optionally, a catalyst. In these embodiments, the signalarising from the direct or indirect electrolysis of the product compoundF at the working electrode corresponds directly to the level of theanalyte (unless there are other sources of the product compound). As thelevel of analyte increases, the level of the product compound and signalat the working electrode increases.

Those skilled in the art will recognize that there are many differentreactions that will achieve the same result; namely the electrolysis ofan analyte or a compound whose level depends on the level of theanalyte. Reaction equations (1) through (6) illustrate non-limitingexamples of such reactions.

Temperature Probe

A variety of optional items may be included in the sensor. One optionalitem is a temperature probe 66 (FIGS. 8 and 11). The temperature probe66 may be made using a variety of known designs and materials. Oneexemplary temperature probe 66 is formed using two probe leads 68, 70connected to each other through a temperature-dependent element 72 thatis formed using a material with a temperature-dependent characteristic.An example of a suitable temperature-dependent characteristic is theresistance of the temperature-dependent element 72.

The two probe leads 68, 70 are typically formed using a metal, an alloy,a semimetal, such as graphite, a degenerate or highly dopedsemiconductor, or a small-band gap semiconductor. Examples of suitablematerials include gold, silver, ruthenium oxide, titanium nitride,titanium dioxide, indium doped tin oxide, tin doped indium oxide, orgraphite. The temperature-dependent element 72 is typically made using afine trace (e.g., a conductive trace that has a smaller cross-sectionthan that of the probe leads 68, 70) of the same conductive material asthe probe leads, or another material such as a carbon ink, a carbonfiber, or platinum, which has a temperature-dependent characteristic,such as resistance, that provides a temperature-dependent signal when avoltage source is attached to the two probe leads 68, 70 of thetemperature probe 66. The temperature-dependent characteristic of thetemperature-dependent element 72 may either increase or decrease withtemperature. Preferably, the temperature dependence of thecharacteristic of the temperature-dependent element 72 is approximatelylinear with temperature over the expected range of biologicaltemperatures (about 25 to 45° C.), although this is not required.

Typically, a signal (e.g., a current) having an amplitude or otherproperty that is a function of the temperature can be obtained byproviding a potential across the two probe leads 68, 70 of thetemperature probe 66. As the temperature changes, thetemperature-dependent characteristic of the temperature-dependentelement 72 increases or decreases with a corresponding change in thesignal amplitude. The signal from the temperature probe 66 (e.g., theamount of current flowing through the probe) may be combined with thesignal obtained from the working electrode 58 by, for example, scalingthe temperature probe signal and then adding or subtracting the scaledtemperature probe signal from the signal at the working electrode 58. Inthis manner, the temperature probe 66 can provide a temperatureadjustment for the output from the working electrode 58 to offset thetemperature dependence of the working electrode 58.

One embodiment of the temperature probe includes probe leads 68, 70formed as two spaced-apart channels with a temperature-dependent element72 formed as a cross-channel connecting the two spaced-apart channels,as illustrated in FIG. 8. The two spaced-apart channels contain aconductive material, such as a metal, alloy, semimetal, degeneratesemiconductor, or metallic compound. The cross-channel may contain thesame material (provided the cross-channel has a smaller cross-sectionthan the two spaced-apart channels) as the probe leads 68, 70. In otherembodiments, the material in the cross-channel is different than thematerial of the probe leads 68, 70.

One exemplary method for forming this particular temperature probeincludes forming the two spaced-apart channels and then filling themwith the metallic or alloyed conductive material. Next, thecross-channel is formed and then filled with the desired material. Thematerial in the cross-channel overlaps with the conductive material ineach of the two spaced-apart channels to form an electrical connection.

For proper operation of the temperature probe 66, thetemperature-dependent element 72 of the temperature probe 66 can not beshorted by conductive material formed between the two probe leads 68,70. In addition, to prevent conduction between the two probe leads 68,70 by ionic species within the body or sample fluid, a covering may beprovided over the temperature-dependent element 72, and preferably overthe portion of the probe leads 68, 70 that is implanted in the patient.The covering may be, for example, a non-conducting film disposed overthe temperature-dependent element 72 and probe leads 68, 70 to preventthe ionic conduction. Suitable non-conducting films include, forexample, Kapton™ polyimide films (DuPont, Wilmington, Del.).

Another method for eliminating or reducing conduction by ionic speciesin the body or sample fluid is to use an ac voltage source connected tothe probe leads 68, 70. In this way, the positive and negative ionicspecies are alternately attracted and repelled during each half cycle ofthe ac voltage. This results in no net attraction of the ions in thebody or sample fluid to the temperature probe 66. The maximum amplitudeof the ac current through the temperature-dependent element 72 may thenbe used to correct the measurements from the working electrodes 58.

The temperature probe can be placed on the same substrate as theelectrodes. Alternatively, a temperature probe may be placed on aseparate substrate. In addition, the temperature probe may be used byitself or in conjunction with other devices.

Another embodiment of a temperature probe utilizes the temperaturedependence of the conductivity of a solution (e.g., blood orinterstitial fluid). Typically, the conductivity of anelectrolyte-containing solution is dependent on the temperature of thesolution, assuming that the concentration of electrolytes is relativelyconstant. Blood, interstitial fluid, and other bodily fluids aresolutions with relatively constant levels of electrolytes. Thus, asensor 42 can include two or more conductive traces (not shown) whichare spaced apart by a known distance. A portion of these conductivetraces is exposed to the solution and the conductivity between theexposed portions of the conductive traces is measured using knowntechniques (e.g., application of a constant or known current orpotential and measurement of the resulting potential or current,respectively, to determine the conductivity).

A change in conductivity is related to a change in temperature. Thisrelation can be modeled using linear, quadratic, exponential, or otherrelations. The parameters for this relationship typically do not varysignificantly between most people. The calibration for the temperatureprobe can be determined by a variety of methods, including, for example,calibration of each sensor 42 using an independent method of determiningtemperature (e.g., a thermometer, an optical or electrical temperaturedetector, or the temperature probe 66, described above) or calibratingone sensor 42 and using that calibration for all other sensors in abatch based on uniformity in geometry.

Biocompatible Layer

An optional film layer 75 is formed over at least that portion of thesensor 42 which is subcutaneously inserted into the patient, as shown inFIG. 9. This optional film layer 74 may serve one or more functions. Thefilm layer 74 prevents the penetration of large biomolecules into theelectrodes. This is accomplished by using a film layer 74 having a poresize that is smaller than the biomolecules that are to be excluded. Suchbiomolecules may foul the electrodes and/or the sensing layer 64 therebyreducing the effectiveness of the sensor 42 and altering the expectedsignal amplitude for a given analyte concentration. The fouling of theworking electrodes 58 may also decrease the effective life of the sensor42. The biocompatible layer 74 may also prevent protein adhesion to thesensor 42, formation of blood clots, and other undesirable interactionsbetween the sensor 42 and body.

For example, the sensor may be completely or partially coated on itsexterior with a biocompatible coating. A preferred biocompatible coatingis a hydrogel which contains at least 20 wt. % fluid when in equilibriumwith the analyte-containing fluid. Examples of suitable hydrogels aredescribed in U.S. Pat. No. 5,593,852, incorporated herein by reference,and include crosslinked polyethylene oxides, such as polyethylene oxidetetraacrylate.

Interferent-Eliminating Layer

An interferent-eliminating layer (not shown) may be included in thesensor 42. The interferent-eliminating layer may be incorporated in thebiocompatible layer 75 or in the mass transport limiting layer 74(described below) or may be a separate layer. Interferents are moleculesor other species that are electroreduced or electrooxidized at theelectrode, either directly or via an electron transfer agent, to producea false signal. In one embodiment, a film or membrane prevents thepenetration of one or more interferents into the region around theworking electrodes 58. Preferably, this type of interferent-eliminatinglayer is much less permeable to one or more of the interferents than tothe analyte.

The interferent-eliminating layer may include ionic components, such asNafion®, incorporated into a polymeric matrix to reduce the permeabilityof the interferent-eliminating layer to ionic interferents having thesame charge as the ionic components. For example, negatively chargedcompounds or compounds that form negative ions may be incorporated inthe interferent-eliminating layer to reduce the permeation of negativespecies in the body or sample fluid.

Another example of an interferent-eliminating layer includes a catalystfor catalyzing a reaction which removes interferents. One example ofsuch a catalyst is a peroxidase. Hydrogen peroxide reacts withinterferents, such as acetaminophen, urate, and ascorbate. The hydrogenperoxide may be added to the analyte-containing fluid or may begenerated in situ, by, for example, the reaction of glucose or lactatein the presence of glucose oxidase or lactate oxidase, respectively.Examples of interferent eliminating layers include a peroxidase enzymecrosslinked (a) using gluteraldehyde as a crosslinking agent or (b)oxidation of oligosaccharide groups in the peroxidase glycoenzyme withNaIO₄, followed by coupling of the aldehydes formed to hydrazide groupsin a polyacrylamide matrix to form hydrazones are describe in U.S. Pat.Nos. 5,262,305 and 5,356,786, incorporated herein by reference.

Mass Transport Limiting Layer

A mass transport limiting layer 74 may be included with the sensor toact as a diffusion-limiting barrier to reduce the rate of mass transportof the analyte, for example, glucose or lactate, into the region aroundthe working electrodes 58. By limiting the diffusion of the analyte, thesteady state concentration of the analyte in the proximity of theworking electrode 58 (which is proportional to the concentration of theanalyte in the body or sample fluid) can be reduced. This extends theupper range of analyte concentrations that can still be accuratelymeasured and may also expand the range in which the current increasesapproximately linearly with the level of the analyte.

It is preferred that the permeability of the analyte through the filmlayer 74 vary little or not at all with temperature, so as to reduce oreliminate the variation of current with temperature. For this reason, itis preferred that in the biologically relevant temperature range fromabout 25° C. to about 45° C., and most importantly from 30° C. to 40°C., neither the size of the pores in the film nor its hydration orswelling change excessively. Preferably, the mass transport limitinglayer is made using a film that absorbs less than 5 wt. % of fluid over24 hours. This may reduce or obviate any need for a temperature probe.For implantable sensors, it is preferable that the mass transportlimiting layer is made using a film that absorbs less than 5 wt. % offluid over 24 hours at 37° C.

Particularly useful materials for the film layer 74 are membranes thatdo not swell in the analyte-containing fluid that the sensor tests.Suitable membranes include 3 to 20,000 nm diameter pores. Membraneshaving 5 to 500 nm diameter pores with well-defined, uniform pore sizesand high aspect ratios are preferred. In one embodiment, the aspectratio of the pores is preferably two or greater and more preferably fiveor greater.

Well-defined and uniform pores can be made by track etching a polymericmembrane using accelerated electrons, ions, or particles emitted byradioactive nuclei. Most preferred are anisotropic, polymeric, tracketched membranes that expand less in the direction perpendicular to thepores than in the direction of the pores when heated. Suitable polymericmembranes included polycarbonate membranes from Poretics (Livermore,Calif., catalog number 19401, 0.01 μm pore size polycarbonate membrane)and Corning Costar Corp. (Cambridge, Mass., Nucleopore™ brand membraneswith 0.015 μm pore size). Other polyolefin and polyester films may beused. It is preferred that the permeability of the mass transportlimiting membrane changes no more than 4%, preferably, no more than 3%,and, more preferably, no more than 2%, per ° C. in the range from 30° C.to 40° C. when the membranes resides in the subcutaneous interstitialfluid.

In some embodiments of the disclosure, the mass transport limiting layer74 may also limit the flow of oxygen into the sensor 42. This canimprove the stability of sensors 42 that are used in situations wherevariation in the partial pressure of oxygen causes non-linearity insensor response. In these embodiments, the mass transport limiting layer74 restricts oxygen transport by at least 40%, preferably at least 60%,and more preferably at least 80%, than the membrane restricts transportof the analyte. For a given type of polymer, films having a greaterdensity (e.g., a density closer to that of the crystalline polymer) arepreferred. Polyesters, such as polyethylene terephthalate, are typicallyless permeable to oxygen and are, therefore, preferred overpolycarbonate membranes.

Anticlotting Agent

An implantable sensor may also, optionally, have an anticlotting agentdisposed on a portion the substrate which is implanted into a patient.This anticlotting agent may reduce or eliminate the clotting of blood orother body fluid around the sensor, particularly after insertion of thesensor. Blood clots may foul the sensor or irreproducibly reduce theamount of analyte which diffuses into the sensor. Examples of usefulanticlotting agents include heparin and tissue plasminogen activator(TPA), as well as other known anticlotting agents.

The anticlotting agent may be applied to at least a portion of that partof the sensor 42 that is to be implanted. The anticlotting agent may beapplied, for example, by bath, spraying, brushing, or dipping. Theanticlotting agent is allowed to dry on the sensor 42. The anticlottingagent may be immobilized on the surface of the sensor or it may beallowed to diffuse away from the sensor surface. Typically, thequantities of anticlotting agent disposed on the sensor are far belowthe amounts typically used for treatment of medical conditions involvingblood clots and, therefore, have only a limited, localized effect.

Sensor Lifetime

The sensor 42 may be designed to be a replaceable component in an invivo analyte monitor, and particularly in an implantable analytemonitor. Typically, the sensor 42 is capable of operation over a periodof days. Preferably, the period of operation is at least one day, morepreferably at least three days, and most preferably at least one week.The sensor 42 can then be removed and replaced with a new sensor. Thelifetime of the sensor 42 may be reduced by the fouling of theelectrodes or by the leaching of the electron transfer agent orcatalyst. These limitations on the longevity of the sensor 42 can beovercome by the use of a biocompatible layer 75 or non-leachableelectron transfer agent and catalyst, respectively, as described above.

Another primary limitation on the lifetime of the sensor 42 is thetemperature stability of the catalyst. Many catalysts are enzymes, whichare very sensitive to the ambient temperature and may degrade attemperatures of the patient's body (e.g., approximately 37° C. for thehuman body). Thus, robust enzymes should be used where available. Thesensor 42 should be replaced when a sufficient amount of the enzyme hasbeen deactivated to introduce an unacceptable amount of error in themeasurements.

Insertion Device

An insertion device 120 can be used to subcutaneously insert the sensor42 into the patient, as illustrated in FIG. 12. The insertion device 120is typically formed using structurally rigid materials, such as metal orrigid plastic. Preferred materials include stainless steel and ABS(acrylonitrile-butadiene-styrene) plastic. In some embodiments, theinsertion device 120 is pointed and/or sharp at the tip 121 tofacilitate penetration of the skin of the patient. A sharp, thininsertion device may reduce pain felt by the patient upon insertion ofthe sensor 42. In other embodiments, the tip 121 of the insertion device120 has other shapes, including a blunt or flat shape. These embodimentsmay be particularly useful when the insertion device 120 does notpenetrate the skin but rather serves as a structural support for thesensor 42 as the sensor 42 is pushed into the skin.

The insertion device 120 may have a variety of cross-sectional shapes,as shown in FIGS. 13A, 13B, and 13C. The insertion device 120illustrated in FIG. 13A is a flat, planar, pointed strip of rigidmaterial which may be attached or otherwise coupled to the sensor 42 toease insertion of the sensor 42 into the skin of the patient, as well asto provide structural support to the sensor 42 during insertion. Theinsertion devices 120 of FIGS. 13B and 13C are U- or V-shaped implementsthat support the sensor 42 to limit the amount that the sensor 42 maybend or bow during insertion. The cross-sectional width 124 of theinsertion devices 120 illustrated in FIGS. 13B and 13C is typically 1 mmor less, preferably 700 μm or less, more preferably 500 μm or less, andmost preferably 300 μm or less. The cross-sectional height 126 of theinsertion device 120 illustrated in FIGS. 13B and 13C is typically about1 mm or less, preferably about 700 μm or less, and more preferably about500 μm or less.

The sensor 42 itself may include optional features to facilitateinsertion. For example, the sensor 42 may be pointed at the tip 123 toease insertion, as illustrated in FIG. 12. In addition, the sensor 42may include a barb 125 which helps retain the sensor 42 in thesubcutaneous tissue of the patient. The barb 125 may also assist inanchoring the sensor 42 within the subcutaneous tissue of the patientduring operation of the sensor 42. However, the barb 125 is typicallysmall enough that little damage is caused to the subcutaneous tissuewhen the sensor 42 is removed for replacement. The sensor 42 may alsoinclude a notch 127 that can be used in cooperation with a correspondingstructure (not shown) in the insertion device to apply pressure againstthe sensor 42 during insertion, but disengage as the insertion device120 is removed. One example of such a structure in the insertion deviceis a rod (not shown) between two opposing sides of an insertion device120 and at an appropriate height of the insertion device 120.

In operation, the sensor 42 is placed within or next to the insertiondevice 120 and then a force is provided against the insertion device 120and/or sensor 42 to carry the sensor 42 into the skin of the patient. Inone embodiment, the force is applied to the sensor 42 to push the sensorinto the skin, while the insertion device 120 remains stationary andprovides structural support to the sensor 42. Alternatively, the forceis applied to the insertion device 120 and optionally to the sensor 42to push a portion of both the sensor 42 and the insertion device 120through the skin of the patient and into the subcutaneous tissue. Theinsertion device 120 is optionally pulled out of the skin andsubcutaneous tissue with the sensor 42 remaining in the subcutaneoustissue due to frictional forces between the sensor 42 and the patient'stissue. If the sensor 42 includes the optional barb 125, then thisstructure may also facilitate the retention of the sensor 42 within theinterstitial tissue as the barb catches in the tissue.

The force applied to the insertion device 120 and/or the sensor 42 maybe applied manually or mechanically. Preferably, the sensor 42 isreproducibly inserted through the skin of the patient. In oneembodiment, an insertion gun is used to insert the sensor. One exampleof an insertion gun 200 for inserting a sensor 42 is shown in FIG. 26.The insertion gun 200 includes a housing 202 and a carrier 204. Theinsertion device 120 is typically mounted on the carrier 204 and thesensor 42 is pre-loaded into the insertion device 120. The carrier 204drives the sensor 42 and, optionally, the insertion device 120 into theskin of the patient using, for example, a cocked or wound spring, aburst of compressed gas, an electromagnet repelled by a second magnet,or the like, within the insertion gun 200. In some instances, forexample, when using a spring, the carrier 204 and insertion device maybe moved, cocked, or otherwise prepared to be directed towards the skinof the patient.

After the sensor 42 is inserted, the insertion gun 200 may contain amechanism which pulls the insertion device 120 out of the skin of thepatient. Such a mechanism may use a spring, electromagnet, or the liketo remove the insertion device 120.

The insertion gun may be reusable. The insertion device 120 is oftendisposable to avoid the possibility of contamination. Alternatively, theinsertion device 120 may be sterilized and reused. In addition, theinsertion device 120 and/or the sensor 42 may be coated with ananticlotting agent to prevent fouling of the sensor 42.

In one embodiment, the sensor 42 is injected between 2 to 12 mm into theinterstitial tissue of the patient for subcutaneous implantation.Preferably, the sensor is injected 3 to 9 mm, and more preferably 5 to 7mm, into the interstitial tissue. Other embodiments of the disclosure,may include sensors implanted in other portions of the patient,including, for example, in an artery, vein, or organ. The depth ofimplantation varies depending on the desired implantation target.

Although the sensor 42 may be inserted anywhere in the body, it is oftendesirable that the insertion site be positioned so that the on-skinsensor control unit 44 can be concealed. In addition, it is oftendesirable that the insertion site be at a place on the body with a lowdensity of nerve endings to reduce the pain to the patient. Examples ofpreferred sites for insertion of the sensor 42 and positioning of theon-skin sensor control unit 44 include the abdomen, thigh, leg, upperarm, and shoulder.

An insertion angle is measured from the plane of the skin (i.e.,inserting the sensor perpendicular to the skin would be a 90° insertionangle). Insertion angles usually range from 10 to 90°, typically from 15to 60°, and often from 30 to 45°.

On-Skin Sensor Control Unit

The on-skin sensor control unit 44 is configured to be placed on theskin of a patient. The on-skin sensor control unit 44 is optionallyformed in a shape that is comfortable to the patient and which maypermit concealment, for example, under a patient's clothing. The thigh,leg, upper arm, shoulder, or abdomen are convenient parts of thepatient's body for placement of the on-skin sensor control unit 44 tomaintain concealment. However, the on-skin sensor control unit 44 may bepositioned on other portions of the patient's body. One embodiment ofthe on-skin sensor control unit 44 has a thin, oval shape to enhanceconcealment, as illustrated in FIGS. 14-16. However, other shapes andsizes may be used.

The particular profile, as well as the height, width, length, weight,and volume of the on-skin sensor control unit 44 may vary and depends,at least in part, on the components and associated functions included inthe on-skin sensor control unit 44, as discussed below. For example, insome embodiments, the on-skin sensor control unit 44 has a height of 1.3cm or less, and preferably 0.7 cm or less. In some embodiments, theon-skin sensor control unit 44 has a weight of 90 grams or less,preferably 45 grams or less, and more preferably 25 grams or less. Insome embodiments, the on-skin sensor control unit 44 has a volume ofabout 15 cm³ or less, preferably about 10 cm³ or less, more preferablyabout 5 cm³ or less, and most preferably about 2.5 cm³ or less.

The on-skin sensor control unit 44 includes a housing 45, as illustratedin FIGS. 14-16. The housing 45 is typically formed as a single integralunit that rests on the skin of the patient. The housing 45 typicallycontains most or all of the electronic components, described below, ofthe on-skin sensor control unit 44. The on-skin sensor control unit 44usually includes no additional cables or wires to other electroniccomponents or other devices. If the housing includes two or more parts,then those parts typically fit together to form a single integral unit.

The housing 45 of the on-skin sensor control unit 44, illustrated inFIGS. 14-16, may be formed using a variety of materials, including, forexample, plastic and polymeric materials, particularly rigidthermoplastics and engineering thermoplastics. Suitable materialsinclude, for example, polyvinyl chloride, polyethylene, polypropylene,polystyrene, ABS polymers, and copolymers thereof. The housing 45 of theon-skin sensor control unit 44 may be formed using a variety oftechniques including, for example, injection molding, compressionmolding, casting, and other molding methods. Hollow or recessed regionsmay be formed in the housing 45 of the on-skin sensor control unit 44.The electronic components of the on-skin sensor control unit 44,described below, and/or other items, such as a battery or a speaker foran audible alarm, may be placed in the hollow or recessed areas.

In some embodiments, conductive contacts 80 are provided on the exteriorof the housing 45. In other embodiments, the conductive contacts 80 areprovided on the interior of the housing 45, for example, within a hollowor recessed region.

In some embodiments, the electronic components and/or other items areincorporated into the housing 45 of the on-skin sensor control unit 44as the plastic or polymeric material is molded or otherwise formed. Inother embodiments, the electronic components and/or other items areincorporated into the housing 45 as the molded material is cooling orafter the molded material has been reheated to make it pliable.Alternatively, the electronic components and/or other items may besecured to the housing 45 using fasteners, such as screws, nuts andbolts, nails, staples, rivets, and the like or adhesives, such ascontact adhesives, pressure sensitive adhesives, glues, epoxies,adhesive resins, and the like. In some cases, the electronic componentsand/or other items are not affixed to the housing 45 at all.

In some embodiments, the housing 45 of the on-skin sensor control unit44 is a single piece. The conductive contacts 80 may be formed on theexterior of the housing 45 or on the interior of the housing 45 providedthere is a port 78 in the housing 45 through which the sensor 42 can bedirected to access the conductive contacts 80.

In other embodiments, the housing 45 of the on-skin sensor control unit44 is formed in at least two separate portions that fit together to formthe housing 45, for example, a base 74 and a cover 76, as illustrated inFIGS. 14-16. The two or more portions of the housing 45 may be entirelyseparate from each other. Alternatively, at least some of the two ormore portions of the housing 45 may be connected together, for example,by a hinge, to facilitate the coupling of the portions to form thehousing 45 of the on-skin sensor control unit 44.

These two or more separate portions of the housing 45 of the on-skinsensor control unit 44 may have complementary, interlocking structures,such as, for example, interlocking ridges or a ridge on one componentand a complementary groove on another component, so that the two or moreseparate components may be easily and/or firmly coupled together. Thismay be useful, particularly if the components are taken apart and fittogether occasionally, for example, when a battery or sensor 42 isreplaced. However, other fasteners may also be used to couple the two ormore components together, including, for example, screws, nuts andbolts, nails, staples, rivets, or the like. In addition, adhesives, bothpermanent or temporary, may be used including, for example, contactadhesives, pressure sensitive adhesives, glues, epoxies, adhesiveresins, and the like.

Typically, the housing 45 is at least water resistant to prevent theflow of fluids into contact with the components in the housing,including, for example, the conductive contacts 80. Preferably, thehousing is waterproof. In one embodiment, two or more components of thehousing 45, for example, the base 74 and the cover 76, fit togethertightly to form a hermetic, waterproof, or water resistant seal so thatfluids can not flow into the interior of the on-skin sensor control unit44. This may be useful to avoid corrosion currents and/or degradation ofitems within the on-skin sensor control unit 44, such as the conductivecontacts, the battery, or the electronic components, particularly whenthe patient engages in such activities as showering, bathing, orswimming.

Water resistant, as used herein, means that there is no penetration ofwater through a water resistant seal or housing when immersed in waterat a depth of one meter at sea level. Waterproof, as used herein, meansthat there is no penetration of water through the waterproof seal orhousing when immersed in water at a depth of ten meters, and preferablyfifty meters, at sea level. It is often desirable that the electroniccircuitry, power supply (e.g., battery), and conductive contacts of theon-skin sensor control unit, as well as the contact pads of the sensor,are contained in a water resistant, and preferably, a waterproof,environment.

In addition to the portions of the housing 45, such as the base 74 andcover 76, there may be other individually-formed pieces of the on-skinsensor control unit 44, which may be assembled during or aftermanufacture. One example of an individually-formed piece is a cover forelectronic components that fits a recess in the base 74 or cover 76.Another example is a cover for a battery provided in the base 74 orcover 76. These individually-formed pieces of the on-skin sensor controlunit 44 may be permanently affixed, such as, for example, a cover forelectronic components, or removably affixed, such as, for example, aremovable cover for a battery, to the base 74, cover 76, or othercomponent of the on-skin sensor control unit 44. Methods for affixingthese individually-formed pieces include the use of fasteners, such asscrews, nuts and bolts, staples, nails, rivets, and the like, frictionalfasteners, such as tongue and groove structures, and adhesives, such ascontact adhesives, pressure sensitive adhesives, glues, epoxies,adhesive resins, and the like.

One embodiment of the on-skin sensor control unit 44 is a disposableunit complete with a battery for operating the unit. There are noportions of the unit that the patient needs to open or remove, therebyreducing the size of the unit and simplifying its construction. Theon-skin sensor control unit 44 optionally remains in a sleep mode priorto use to conserve the battery's power. The on-skin sensor control unit44 detects that it is being used and activates itself. Detection of usemay be through a number of mechanisms. These include, for example,detection of a change in resistance across the electrical contacts,actuation of a switch upon mating the on-skin sensor control unit 44with a mounting unit 77 (see FIGS. 27A and 28A). The on-skin sensorcontrol unit 44 is typically replaced when it no longer operates withinthreshold limits, for example, if the battery or other power source doesnot generate sufficient power. Often this embodiment of the on-skinsensor control unit 44 has conductive contacts 80 on the exterior of thehousing 45. Once the sensor 42 is implanted in the patient, the sensorcontrol unit 44 is placed over the sensor 42 with the conductivecontacts 80 in contact with the contact pads 49 of the sensor 42.

The on-skin sensor control unit 44 is typically attached to the skin 75of the patient, as illustrated in FIG. 17. The on-skin sensor controlunit 44 may be attached by a variety of techniques including, forexample, by adhering the on-skin sensor control unit 44 directly to theskin 75 of the patient with an adhesive provided on at least a portionof the housing 45 of the on-skin sensor control unit 44 which contactsthe skin 75 or by suturing the on-skin sensor control unit 44 to theskin 75 through suture openings (not shown) in the sensor control unit44.

Another method of attaching the housing 45 of the on-skin sensor controlunit 44 to the skin 75 includes using a mounting unit, 77. The mountingunit 77 is often a part of the on-skin sensor control unit 44. Oneexample of a suitable mounting unit 77 is a double-sided adhesive strip,one side of which is adhered to a surface of the skin of the patient andthe other side is adhered to the on-skin sensor control unit 44. In thisembodiment, the mounting unit 77 may have an optional opening 79 whichis large enough to allow insertion of the sensor 42 through the opening79. Alternatively, the sensor may be inserted through a thin adhesiveand into the skin.

A variety of adhesives may be used to adhere the on-skin sensor controlunit 44 to the skin 75 of the patient, either directly or using themounting unit 77, including, for example, pressure sensitive adhesives(PSA) or contact adhesives. Preferably, an adhesive is chosen which isnot irritating to all or a majority of patients for at least the periodof time that a particular sensor 42 is implanted in the patient.Alternatively, a second adhesive or other skin-protecting compound maybe included with the mounting unit so that a patient, whose skin isirritated by the adhesive on the mounting unit 77, can cover his skinwith the second adhesive or other skin-protecting compound and thenplace the mounting unit 77 over the second adhesive or otherskin-protecting compound. This should substantially prevent theirritation of the skin of the patient because the adhesive on themounting unit 77 is no longer in contact with the skin, but is insteadin contact with the second adhesive or other skin-protecting compound.

When the sensor 42 is changed, the on-skin sensor control unit 44 may bemoved to a different position on the skin 75 of the patient, forexample, to avoid excessive irritation. Alternatively, the on-skinsensor control unit 44 may remain at the same place on the skin of thepatient until it is determined that the unit 44 should be moved.

Another embodiment of a mounting unit 77 used in an on-skin sensorcontrol unit 44 is illustrated in FIGS. 27A and 27B. The mounting unit77 and a housing 45 of an on-skin sensor control unit 44 are mountedtogether in, for example, an interlocking manner, as shown in FIG. 27A.The mounting unit 77 is formed, for example, using plastic or polymermaterials, including, for example, polyvinyl chloride, polyethylene,polypropylene, polystyrene, ABS polymers, and copolymers thereof. Themounting unit 77 may be formed using a variety of techniques including,for example, injection molding, compression molding, casting, and othermolding methods.

The mounting unit 77 typically includes an adhesive on a bottom surfaceof the mounting unit 77 to adhere to the skin of the patient or themounting unit 77 is used in conjunction with, for example, double-sidedadhesive tape or the like. The mounting unit 77 typically includes anopening 79 through which the sensor 42 is inserted, as shown in FIG.27B. The mounting unit 77 may also include a support structure 220 forholding the sensor 42 in place and against the conductive contacts 80 onthe on-skin sensor control unit 42. The mounting unit 77, also,optionally, includes a positioning structure 222, such as an extensionof material from the mounting unit 77, that corresponds to a structure(not shown), such as an opening, on the sensor 42 to facilitate properpositioning of the sensor 42, for example, by aligning the twocomplementary structures.

In another embodiment, a coupled mounting unit 77 and housing 45 of anon-skin sensor control unit 44 is provided on an adhesive patch 204 withan optional cover 206 to protect and/or confine the housing 45 of theon-skin sensor control unit 44, as illustrated in FIG. 28A. The optionalcover may contain an adhesive or other mechanism for attachment to thehousing 45 and/or mounting unit 77. The mounting unit 77 typicallyincludes an opening 49 through which a sensor 42 is disposed, as shownin FIG. 28B. The opening 49 may optionally be configured to allowinsertion of the sensor 42 through the opening 49 using an insertiondevice 120 or insertion gun 200 (see FIG. 26). The housing 45 of theon-skin sensor control unit 44 has a base 74 and a cover 76, asillustrated in FIG. 28C. A bottom view of the housing 45, as shown inFIG. 28D, illustrates ports 230 through which conductive contacts (notshown) extend to connect with contact pads on the sensor 42. A board 232for attachment of circuit components may optionally be provided withinthe on-skin sensor control unit 44, as illustrated in FIG. 28E.

In some embodiments, the adhesive on the on-skin sensor control unit 44and/or on any of the embodiments of the mounting unit 77 is waterresistant or waterproof to permit activities such as showering and/orbathing while maintaining adherence of the on-skin sensor control unit44 to the skin 75 of the patient and, at least in some embodiments,preventing water from penetrating into the sensor control unit 44. Theuse of a water resistant or waterproof adhesive combined with a waterresistant or waterproof housing 45 protects the components in the sensorcontrol unit 44 and the contact between the conductive contacts 80 andthe sensor 42 from damage or corrosion. An example of a non-irritatingadhesive that repels water is Tegaderm (3M, St. Paul, Minn.).

In one embodiment, the on-skin sensor control unit 44 includes a sensorport 78 through which the sensor 42 enters the subcutaneous tissue ofthe patient, as shown in FIGS. 14 to 16. The sensor 42 may be insertedinto the subcutaneous tissue of the patient through the sensor port 78.The on-skin sensor control unit 44 may then be placed on the skin of thepatient with the sensor 42 being threaded through the sensor port 78. Ifthe housing 45 of the sensor 42 has, for example, a base 74 and a cover76, then the cover 76 may be removed to allow the patient to guide thesensor 42 into the proper position for contact with the conductivecontacts 80.

Alternatively, if the conductive contacts 80 are within the housing 45the patient may slide the sensor 42 into the housing 45 until contact ismade between the contact pads 49 and the conductive contacts 80. Thesensor control unit 44 may have a structure which obstructs the slidingof the sensor 42 further into the housing once the sensor 42 is properlypositioned with the contact pads 49 in contact with the conductivecontacts 80.

In other embodiments, the conductive contacts 80 are on the exterior ofthe housing 45 (see e.g., FIGS. 27A-27B and 28A-28E). In theseembodiments, the patient guides the contacts pads 49 of the sensor 42into contact with the conductive contacts 80. In some cases, a guidingstructure may be provided on the housing 45 which guides the sensor 42into the proper position. An example of such a structure includes a setof guiding rails extending from the housing 45 and having the shape ofthe sensor 42.

In some embodiments, when the sensor 42 is inserted using an insertiondevice 120 (see FIG. 12), the tip of the insertion device 120 oroptional insertion gun 200 (see FIG. 26) is positioned against the skinor the mounting unit 77 at the desired insertion point. In someembodiments, the insertion device 120 is positioned on the skin withoutany guide. In other embodiments, the insertion device 120 or insertiongun 200 is positioned using guides (not shown) in the mounting unit 77or other portion of the on-skin sensor control unit 44. In someembodiments, the guides, opening 79 in the mounting unit 77 and/orsensor port 78 in the housing 45 of the on-skin sensor control unit 44have a shape which is complementary to the shape of the tip of theinsertion device 120 and/or insertion gun 200 to limit the orientationof the insertion device 120 and/or insertion gun 200 relative to theopening 79 and/or sensor port 78. The sensor can then be subcutaneouslyinserted into the patient by matching the complementary shape of theopening 79 or sensor port 78 with the insertion device 120 and/orinsertion gun 200.

In some embodiments, the shapes of a) the guides, opening 79, or sensorport 78, and (b) the insertion device 120 or insertion gun 200 areconfigured such that the two shapes can only be matched in a singleorientation. This aids in inserting the sensor 42 in the sameorientation each time a new sensor is inserted into the patient. Thisuniformity in insertion orientation may be required in some embodimentsto ensure that the contact pads 49 on the sensor 42 are correctlyaligned with appropriate conductive contacts 80 on the on-skin sensorcontrol unit 44. In addition, the use of the insertion gun, as describedabove, may ensure that the sensor 42 is inserted at a uniform,reproducible depth.

The sensor 42 and the electronic components within the on-skin sensorcontrol unit 44 are coupled via conductive contacts 80, as shown inFIGS. 14-16. The one or more working electrodes 58, counter electrode 60(or counter/reference electrode), optional reference electrode 62, andoptional temperature probe 66 are attached to individual conductivecontacts 80. In the illustrated embodiment of FIGS. 14-16, theconductive contacts 80 are provided on the interior of the on-skinsensor control unit 44. Other embodiments of the on-skin sensor controlunit 44 have the conductive contacts disposed on the exterior of thehousing 45. The placement of the conductive contacts 80 is such thatthey are in contact with the contact pads 49 on the sensor 42 when thesensor 42 is properly positioned within the on-skin sensor control unit44.

In the illustrated embodiment of FIGS. 14-16, the base 74 and cover 76of the on-skin sensor control unit 44 are formed such that, when thesensor 42 is within the on-skin sensor control unit 44 and the base 74and cover 76 are fitted together, the sensor 42 is bent. In this manner,the contact pads 49 on the sensor 42 are brought into contact with theconductive contacts 80 of the on-skin sensor control unit 44. Theon-skin sensor control unit 44 may optionally contain a supportstructure 82 to hold, support, and/or guide the sensor 42 into thecorrect position.

Non-limiting examples of suitable conductive contacts 80 are illustratedin FIGS. 19A-19D. In one embodiment, the conductive contacts 80 are pins84 or the like, as illustrated in FIG. 19A, which are brought intocontact with the contact pads 49 on the sensor 42 when the components ofthe on-skin sensor control unit 44, for example, the base 74 and cover76, are fitted together. A support 82 may be provided under the sensor42 to promote adequate contact between the contact pads 49 on the sensor42 and the pins 84. The pins are typically made using a conductivematerial, such as a metal or alloy, for example, copper, stainlesssteel, or silver. Each pin has a distal end that extends from theon-skin sensor control unit 44 for contacting the contact pads 49 on thesensor 42. Each pin 84 also has a proximal end that is coupled to a wireor other conductive strip that is, in turn, coupled to the rest of theelectronic components (e.g., the voltage source 95 and measurementcircuit 96 of FIGS. 18A and 18B) within the on-skin sensor control unit44. Alternatively, the pins 84 may be coupled directly to the rest ofthe electronics.

In another embodiment, the conductive contacts 80 are formed as a seriesof conducting regions 88 with interspersed insulating regions 90, asillustrated in FIG. 19B. The conducting regions 88 may be as large orlarger than the contact pads 49 on the sensor 42 to alleviateregistration concerns. However, the insulating regions 90 should havesufficient width so that a single conductive region 88 does not overlapwith two contact pads 49 as determined based on the expected variationin the position of the sensor 42 and contact pads 49 with respect to theconductive contacts 80. The conducting regions 88 are formed usingmaterials such as metals, alloys, or conductive carbon. The insulatingregions 90 may be formed using known insulating materials including, forexample, insulating plastic or polymer materials.

In a further embodiment, a unidirectional conducting adhesive 92 may beused between the contact pads 49 on the sensor 42 and conductivecontacts 80 implanted or otherwise formed in the on-skin sensor controlunit 44, as shown in FIG. 19C.

In yet another embodiment, the conductive contacts 80 are conductivemembers 94 that extend from a surface of the on-skin sensor control unit44 to contact the contact pads 49, as shown in FIG. 19D. A variety ofdifferent shapes may be used for these members, however, they should beelectrically insulated from each other. The conductive members 94 may bemade using metal, alloy, conductive carbon, or conducting plastics andpolymers.

Any of the exemplary conductive contacts 80 described above may extendfrom either the upper surface of the interior of the on-skin sensorcontrol unit 44, as illustrated in FIG. 19A-19C, or from the lowersurface of the interior of the on-skin sensor control unit 44, asillustrated in FIG. 19D, or from both the upper and lower surfaces ofthe interior of the on-skin sensor control unit 44, particularly whenthe sensor 42 has contact pads 49 on both sides of the sensor.

Conductive contacts 80 on the exterior of the housing 45 may also have avariety of shapes as indicated in FIGS. 19E and 19F. For example, theconductive contacts 80 may be embedded in (FIG. 19E) or extending out of(FIG. 19F) the housing 45.

The conductive contacts 80 are preferably made using a material whichwill not corrode due to contact with the contact pads 49 of the sensor42. Corrosion may occur when two different metals are brought incontact. Thus, if the contact pads 49 are formed using carbon then thepreferred conductive contacts 80 may be made using any material,including metals or alloys. However, if any of the contact pads 49 aremade with a metal or alloy then the preferred conductive contacts 80 forcoupling with the metallic contact pads are made using a non-metallicconductive material, such as conductive carbon or a conductive polymer,or the conductive contacts 80 and the contact pads 49 are separated by anon-metallic material, such as a unidirectional conductive adhesive.

In one embodiment, electrical contacts are eliminated between the sensor42 and the on-skin sensor control unit 44. Power is transmitted to thesensor via inductive coupling, using, for example, closely spaceantennas (e.g., facing coils) (not shown) on the sensor and the on-skinsensor control unit. Changes in the electrical characteristics of thesensor control unit 44 (e.g., current) induce a changing magnetic fieldin the proximity of the antenna. The changing magnetic field induces acurrent in the antenna of the sensor. The close proximity of the sensorand on-skin sensor control unit results in reasonably efficient powertransmission. The induced current in the sensor may be used to powerpotentiostats, operational amplifiers, capacitors, integrated circuits,transmitters, and other electronic components built into the sensorstructure. Data is transmitted back to the sensor control unit, using,for example, inductive coupling via the same or different antennasand/or transmission of the signal via a transmitter on the sensor. Theuse of inductive coupling can eliminate electrical contacts between thesensor and the on-skin sensor control unit. Such contacts are commonly asource of noise and failure. Moreover, the sensor control unit may thenbe entirely sealed which may increase the waterproofing of the on-skinsensor control unit.

An exemplary on-skin sensor control unit 44 can be prepared and used inthe following manner. A mounting unit 77 having adhesive on the bottomis applied to the skin. An insertion gun 200 (see FIG. 26) carrying thesensor 42 and the insertion device 120 is positioned against themounting unit 77. The insertion gun 200 and mounting unit 77 areoptionally designed such that there is only one position in which thetwo properly mate. The insertion gun 200 is activated and a portion ofthe sensor 42 and optionally a portion of the insertion device 120 aredriven through the skin into, for example, the subcutaneous tissue. Theinsertion gun 200 withdraws the insertion device 200, leaving theportion of the sensor 42 inserted through the skin. The housing 45 ofthe on-skin control unit 44 is then coupled to the mounting unit 77.Optionally, the housing 45 and the mounting unit 77 are formed such thatthere is only one position in which the two properly mate. The mating ofthe housing 45 and the mounting unit 77 establishes contact between thecontact pads 49 (see e.g., FIG. 2) on the sensor 42 and the conductivecontacts 80 on the on-skin sensor control unit 44. Optionally, thisaction activates the on-skin sensor control unit 44 to begin operation.

On-Skin Control Unit Electronics

The on-skin sensor control unit 44 also typically includes at least aportion of the electronic components that operate the sensor 42 and theanalyte monitoring device system 40. One embodiment of the electronicsin the on-skin control unit 44 is illustrated as a block diagram in FIG.18A. The electronic components of the on-skin sensor control unit 44typically include a power supply 95 for operating the on-skin controlunit 44 and the sensor 42, a sensor circuit 97 for obtaining signalsfrom and operating the sensor 42, a measurement circuit 96 that convertssensor signals to a desired format, and a processing circuit 109 that,at minimum, obtains signals from the sensor circuit 97 and/ormeasurement circuit 96 and provides the signals to an optionaltransmitter 98. In some embodiments, the processing circuit 109 may alsopartially or completely evaluate the signals from the sensor 42 andconvey the resulting data to the optional transmitter 98 and/or activatean optional alarm system 94 (see FIG. 18B) if the analyte level exceedsa threshold. The processing circuit 109 often includes digital logiccircuitry.

The on-skin sensor control unit 44 may optionally contain a transmitter98 for transmitting the sensor signals or processed data from theprocessing circuit 109 to a receiver/display unit 46, 48; a data storageunit 102 for temporarily or permanently storing data from the processingcircuit 109; a temperature probe circuit 99 for receiving signals fromand operating a temperature probe 66; a reference voltage generator 101for providing a reference voltage for comparison with sensor-generatedsignals; and/or a watchdog circuit 103 that monitors the operation ofthe electronic components in the on-skin sensor control unit 44.

Moreover, the sensor control unit 44 often includes digital and/oranalog components utilizing semiconductor devices, such as transistors.To operate these semiconductor devices, the on-skin control unit 44 mayinclude other components including, for example, a bias controlgenerator 105 to correctly bias analog and digital semiconductordevices, an oscillator 107 to provide a clock signal, and a digitallogic and timing component 109 to provide timing signals and logicoperations for the digital components of the circuit.

As an example of the operation of these components, the sensor circuit97 and the optional temperature probe circuit 99 provide raw signalsfrom the sensor 42 to the measurement circuit 96. The measurementcircuit 96 converts the raw signals to a desired format, using forexample, a current-to-voltage converter, current-to-frequency converter,and/or a binary counter or other indicator that produces a signalproportional to the absolute value of the raw signal. This may be used,for example, to convert the raw signal to a format that can be used bydigital logic circuits. The processing circuit 109 may then, optionally,evaluate the data and provide commands to operate the electronics.

FIG. 18B illustrates a block diagram of another exemplary on-skincontrol unit 44 that also includes optional components such as areceiver 99 to receive, for example, calibration data; a calibrationstorage unit 100 to hold, for example, factory-set calibration data,calibration data obtained via the receiver 99 and/or operational signalsreceived, for example, from a receiver/display unit 46, 48 or otherexternal device; an alarm system 104 for warning the patient; and adeactivation switch 111 to turn off the alarm system.

Functions of the analyte monitoring system 40 and the sensor controlunit 44 may be implemented using either software routines, hardwarecomponents, or combinations thereof. The hardware components may beimplemented using a variety of technologies, including, for example,integrated circuits or discrete electronic components. The use ofintegrated circuits typically reduces the size of the electronics, whichin turn may result in a smaller on-skin sensor control unit 44.

The electronics in the on-skin sensor control unit 44 and the sensor 42are operated using a power supply 95. One example of a suitable powersupply 95 is a battery, for example, a thin circular battery, such asthose used in many watches, hearing aids, and other small electronicdevices. Preferably, the battery has a lifetime of at least 30 days,more preferably, a lifetime of at least three months, and mostpreferably, a lifetime of at least one year. The battery is often one ofthe largest components in the on-skin control unit 44, so it is oftendesirable to minimize the size of the battery. For example, a preferredbattery's thickness is 0.5 mm or less, preferably 0.35 mm or less, andmost preferably 0.2 mm or less. Although multiple batteries may be used,it is typically preferred to use only one battery.

The sensor circuit 97 is coupled via the conductive contacts 80 of thesensor control unit 44 to one or more sensors 42, 42′. Each of thesensors represents, at minimum, a working electrode 58, a counterelectrode 60 (or counter/reference electrode), and an optional referenceelectrode 62. When two or more sensors 42, 42′ are used, the sensorstypically have individual working electrodes 58, but may share a counterelectrode 60, counter/reference electrode, and/or reference electrode52.

The sensor circuit 97 receives signals from and operates the sensor 42or sensors 42, 42′. The sensor circuit 97 may obtain signals from thesensor 42 using amperometric, coulometric, potentiometric, voltammetric,and/or other electrochemical techniques. The sensor circuit 97 isexemplified herein as obtaining amperometric signals from the sensor 42,however, it will be understood that the sensor circuit can beappropriately configured for obtaining signals using otherelectrochemical techniques. To obtain amperometric measurements, thesensor circuit 97 typically includes a potentiostat that provides aconstant potential to the sensor 42. In other embodiments, the sensorcircuit 97 includes an amperostat that supplies a constant current tothe sensor 42 and can be used to obtain coulometric or potentiometricmeasurements.

The signal from the sensor 42 generally has at least one characteristic,such as, for example, current, voltage, or frequency, which varies withthe concentration of the analyte. For example, if the sensor circuit 97operates using amperometry, then the signal current varies with analyteconcentration. The measurement circuit 96 may include circuitry whichconverts the information-carrying portion of the signal from onecharacteristic to another. For example, the measurement circuit 96 mayinclude a current-to-voltage or current-to-frequency converter. Thepurpose of this conversion may be to provide a signal that is, forexample, more easily transmitted, readable by digital circuits, and/orless susceptible to noise contributions.

One example of a standard current-to-voltage converter is provided inFIG. 20A. In this converter, the signal from the sensor 42 is providedat one input terminal 134 of an operational amplifier 130 (“op amp”) andcoupled through a resistor 138 to an output terminal 136. Thisparticular current-to-voltage converter 131 may, however, be difficultto implement in a small CMOS chip because resistors are often difficultto implement on an integrated circuit. Typically, discrete resistorcomponents are used. However, the used of discrete components increasesthe space needed for the circuitry.

An alternative current-to-voltage converter 141 is illustrated in FIG.20B. This converter includes an op amp 140 with the signal from thesensor 42 provided at input terminal 144 and a reference potentialprovided at input terminal 142. A capacitor 145 is placed between theinput terminal 144 and the output terminal 146. In addition, switches147 a, 147 b, 149 a, and 149 b are provided to allow the capacitor tocharge and discharge at a rate determined by a clock (CLK) frequency. Inoperation, during one half cycle, switches 147 a and 147 b close andswitches 149 a and 149 b open allowing the capacitor 145 to charge dueto the attached potential Vi. During the other half cycle, switches 147a and 147 b open and switches 149 a and 149 b close to ground and allowthe capacitor 145 to partially or fully discharge. The reactiveimpedance of the capacitor 145 is analogous to the resistance of theresistor 138 (see FIG. 20A), allowing the capacitor 145 to emulate aresistor. The value of this “resistor” depends on the capacitance of thecapacitor 145 and the clock frequency. By altering the clock frequency,the reactive impedance (“resistance value”) of the capacitor changes.The value of the impedance (“resistance”) of the capacitor 145 may bealtered by changing the clock frequency. Switches 147 a, 147 b, 149 a,and 149 b may be implemented in a CMOS chip using, for example,transistors.

A current-to-frequency converter may also be used in the measurementcircuit 96. One suitable current-to-frequency converter includescharging a capacitor using the signal from the sensor 42. When thepotential across the capacitor exceeds a threshold value, the capacitoris allowed to discharge. Thus, the larger the current from the sensor42, the quicker the threshold potential is achieved. This results in asignal across the capacitor that has an alternating characteristic,corresponding to the charging and discharging of the capacitor, having afrequency which increases with an increase in current from the sensor42.

In some embodiments, the analyte monitoring system 40 includes two ormore working electrodes 58 distributed over one or more sensors 42.These working electrodes 58 may be used for quality control purposes.For example, the output signals and/or analyzed data derived using thetwo or more working electrodes 58 may be compared to determine if thesignals from the working electrodes agree within a desired level oftolerance. If the output signals do not agree, then the patient may bealerted to replace the sensor or sensors. In some embodiments, thepatient is alerted only if the lack of agreement between the two sensorspersists for a predetermined period of time. The comparison of the twosignals may be made for each measurement or at regular intervals.Alternatively or additionally, the comparison may be initiated by thepatient or another person. Moreover, the signals from both sensors maybe used to generate data or one signal may be discarded after thecomparison.

Alternatively, if, for example, two working electrodes 58 have a commoncounter electrode 60 and the analyte concentration is measured byamperometry, then the current at the counter electrode 60 should betwice the current at each of the working electrodes, within apredetermined tolerance level, if the working electrodes are operatingproperly. If not, then the sensor or sensors should be replaced, asdescribed above.

An example of using signals from only one working electrode for qualitycontrol includes comparing consecutive readings obtained using thesingle working electrode to determine if they differ by more than athreshold level. If the difference is greater than the threshold levelfor one reading or over a period of time or for a predetermined numberof readings within a period of time then the patient is alerted toreplace the sensor 42. Typically, the consecutive readings and/or thethreshold level are determined such that all expected excursions of thesensor signal are within the desired parameters (i.e., the sensorcontrol unit 44 does not consider true changes in analyte concentrationto be a sensor failure).

The sensor control unit 44 may also optionally include a temperatureprobe circuit 99. The temperature probe circuit 99 provides a constantcurrent through (or constant potential) across the temperature probe 66.The resulting potential (or current) varies according to the resistanceof the temperature dependent element 72.

The output from the sensor circuit 97 and optional temperature probecircuit is coupled into a measurement circuit 96 that obtains signalsfrom the sensor circuit 97 and optional temperature probe circuit 99and, at least in some embodiments, provides output data in a form that,for example can be read by digital circuits. The signals from themeasurement circuit 96 are sent to the processing circuit 109, which inturn may provide data to an optional transmitter 98. The processingcircuit 109 may have one or more of the following functions: 1) transferthe signals from the measurement circuit 96 to the transmitter 98, 2)transfer signals from the measurement circuit 96 to the data storagecircuit 102, 3) convert the information-carrying characteristic of thesignals from one characteristic to another (when, for example, that hasnot been done by the measurement circuit 96), using, for example, acurrent-to-voltage converter, a current-to-frequency converter, or avoltage-to-current converter, 4) modify the signals from the sensorcircuit 97 using calibration data and/or output from the temperatureprobe circuit 99, 5) determine a level of an analyte in the interstitialfluid, 6) determine a level of an analyte in the bloodstream based onthe sensor signals obtained from interstitial fluid, 7) determine if thelevel, rate of change, and/or acceleration in the rate of change of theanalyte exceeds or meets one or more threshold values, 8) activate analarm if a threshold value is met or exceeded, 9) evaluate trends in thelevel of an analyte based on a series of sensor signals, 10) determine adose of a medication, and 11) reduce noise and/or errors, for example,through signal averaging or comparing readings from multiple workingelectrodes 58.

The processing circuit 109 may be simple and perform only one or a smallnumber of these functions or the processing circuit 109 may be moresophisticated and perform all or most of these functions. The size ofthe on-skin sensor control unit 44 may increase with the increasingnumber of functions and complexity of those functions that theprocessing circuit 109 performs. Many of these functions may not beperformed by a processing circuit 109 in the on-skin sensor control unit44, but may be performed by another analyzer 152 in the receiver/displayunits 46, 48 (see FIG. 22).

One embodiment of the measurement circuit 96 and/or processing circuit109 provides as output data, the current flowing between the workingelectrode 58 and the counter electrode 60. The measurement circuit 96and/or processing circuit 109 may also provide as output data a signalfrom the optional temperature probe 66 which indicates the temperatureof the sensor 42. This signal from the temperature probe 66 may be assimple as a current through the temperature probe 66 or the processingcircuit 109 may include a device that determines a resistance of thetemperature probe 66 from the signal obtained from the measurementcircuit 96 for correlation with the temperature of the sensor 42. Theoutput data may then be sent to a transmitter 98 that then transmitsthis data to at least one receiver/display device 46,48.

Returning to the processing circuit 109, in some embodiments processingcircuit 109 is more sophisticated and is capable of determining theanalyte concentration or some measure representative of the analyteconcentration, such as a current or voltage value. The processingcircuit 109 may incorporate the signal of the temperature probe to makea temperature correction in the signal or analyzed data from the workingelectrode 58. This may include, for example, scaling the temperatureprobe measurement and adding or subtracting the scaled measurement tothe signal or analyzed data from the working electrode 58. Theprocessing circuit 109 may also incorporate calibration data which hasbeen received from an external source or has been incorporated into theprocessing circuit 109, both of which are described below, to correctthe signal or analyzed data from the working electrode 58. Additionally,the processing circuit 109 may include a correction algorithm forconverting interstitial analyte level to blood analyte level. Theconversion of interstitial analyte level to blood analyte level isdescribed, for example, in Schmidtke, et al., “Measurement and Modelingof the Transient Difference Between Blood and Subcutaneous GlucoseConcentrations in the Rat after Injection of Insulin”, Proc. of theNat'l Acad. of Science, 95, 294-299 (1998) and Quinn, et al., “Kineticsof Glucose Delivery to Subcutaneous Tissue in Rats Measured with 0.3 mmAmperometric Microsensors”, Am. J. Physiol., 269 (Endocrinol. Metab.32), E155-E161 (1995), incorporated herein by reference.

In some embodiments, the data from the processing circuit 109 isanalyzed and directed to an alarm system 94 (see FIG. 18B) to warn theuser. In at least some of these embodiments, a transmitter is not usedas the sensor control unit performs all of the needed functionsincluding analyzing the data and warning the patient.

However, in many embodiments, the data (e.g., a current signal, aconverted voltage or frequency signal, or fully or partially analyzeddata) from processing circuit 109 is transmitted to one or morereceiver/display units 46, 48 using a transmitter 98 in the on-skinsensor control unit 44. The transmitter has an antenna 93, such as awire or similar conductor, formed in the housing 45. The transmitter 98is typically designed to transmit a signal up to about 2 meters or more,preferably up to about 5 meters or more, and more preferably up to about10 meters or more. when transmitting to a small receiver/display unit46, such as a palm-size, belt-worn receiver. The effective range islonger when transmitting to a unit with a better antenna, such as abedside receiver. As described in detail below, suitable examples ofreceiver/display units 46, 48 include units that can be easily worn orcarried or units that can be placed conveniently on, for example, anightstand when the patient is sleeping.

The transmitter 98 may send a variety of different signals to thereceiver/display units 46, 48, typically, depending on thesophistication of the processing circuit 109. For example, theprocessing circuit 109 may simply provide raw signals, for example,currents from the working electrodes 58, without any corrections fortemperature or calibration, or the processing circuit 109 may provideconverted signals which are obtained, for example, using acurrent-to-voltage converter 131 or 141 or a current-to-frequencyconverter. The raw measurements or converted signals may then beprocessed by an analyzer 152 (see FIG. 22) in the receiver/display units46, 48 to determine the level of an analyte, optionally usingtemperature and calibration corrections. In another embodiment, theprocessing circuit 109 corrects the raw measurements using, for example,temperature and/or calibration information and then the transmitter 98sends the corrected signal, and optionally, the temperature and/orcalibration information, to the receiver/display units 46, 48. In yetanother embodiment, the processing circuit 109 calculates the analytelevel in the interstitial fluid and/or in the blood (based on theinterstitial fluid level) and transmits that information to the one ormore receiver/display units 46, 48, optionally with any of the raw dataand/or calibration or temperature information. In a further embodiment,the processing circuit 109 calculates the analyte concentration, but thetransmitter 98 transmits only the raw measurements, converted signals,and/or corrected signals.

One potential difficulty that may be experienced with the on-skin sensorcontrol unit 44 is a change in the transmission frequency of thetransmitter 98 over time. To overcome this potential difficulty, thetransmitter may include optional circuitry that can return the frequencyof the transmitter 98 to the desired frequency or frequency band. Oneexample of suitable circuitry is illustrated in FIG. 21 as a blockdiagram of an open loop modulation system 200. The open loop modulationsystem 200 includes a phase detector (PD) 210, a charge pump (CHGPMP)212, a loop filter (L.F.) 214, a voltage controlled oscillator (VCO)216, and a divide by M circuit (÷M) 218 to form the phase-locked loop220.

The analyte monitoring device 40 uses an open loop modulation system 200for RF communication between the transmitter 98 and a receiver of, forexample, the one or more receiver/display units 46, 48. This open loopmodulation system 230 is designed to provide a high reliability RF linkbetween a transmitter and its associated receiver. The system employsfrequency modulation (FM), and locks the carrier center frequency usinga conventional phase-locked loop (PLL) 220. In operation, thephase-locked loop 220 is opened prior to the modulation. During themodulation the phase-locked loop 220 remains open for as long as thecenter frequency of the transmitter is within the receiver's bandwidth.When the transmitter detects that the center frequency is going to moveoutside of the receiver bandwidth, the receiver is signaled to stand bywhile the center frequency is captured. Subsequent to the capture, thetransmission will resume. This cycle of capturing the center frequency,opening the phase-locked loop 220, modulation, and recapturing thecenter frequency will repeat for as many cycles as required.

The loop control 240 detects the lock condition of the phase-locked loop220 and is responsible for closing and opening the phase-locked loop220. The totalizer 250 in conjunction with the loop control 240, detectsthe status of the center frequency. The modulation control 230 isresponsible for generating the modulating signal. A transmit amplifier260 is provided to ensure adequate transmit signal power. The referencefrequency is generated from a very stable signal source (not shown), andis divided down by N through the divide by N block (÷N) 270. Data andcontrol signals are received by the open loop modulation system 200 viathe DATA BUS 280, and the CONTROL BUS 290.

The operation of the open loop modulation system 200 begins with thephase-locked loop 220 in closed condition. When the lock condition isdetected by the loop control 240, the phase-locked loop 220 is openedand the modulation control 230 begins generating the modulating signal.The totalizer 250 monitors the VCO frequency (divided by M), forprogrammed intervals. The monitored frequency is compared to a thresholdprogrammed in the totalizer 250. This threshold corresponds to the 3 dBcut off frequencies of the receiver's intermediate frequency stage. Whenthe monitored frequency approaches the thresholds, the loop control 240is notified and a stand-by code is transmitted to the receiver and thephase-locked loop 220 is closed.

At this point the receiver is in the wait mode. The loop control 240 inthe transmitter closes the phase-locked loop 220. Then, modulationcontrol 230 is taken off line, the monitored value of the totalizer 250is reset, and the phase-locked loop 220 is locked. When the loop control240 detects a lock condition, the loop control 240 opens thephase-locked loop 220, the modulation control 230 is brought on line andthe data transmission to the receiver will resume until the centerfrequency of the phase-locked loop 220 approaches the threshold values,at which point the cycle of transmitting the stand-by code begins. The÷N 270 and ÷M 218 block set the frequency channel of the transmitter.

Accordingly, the open loop modulation system 200 provides a reliable lowpower FM data transmission for an analyte monitoring system. The openloop modulation system 200 provides a method of wide band frequencymodulation, while the center frequency of the carrier is kept withinreceiver bandwidth. The effect of parasitic capacitors and inductorspulling the center frequency of the transmitter is corrected by thephase-locked loop 220. Further, the totalizer 250 and loop control 240provide a new method of center frequency drift detection. Finally, theopen loop modulation system 200 is easily implemented in CMOS process.

The rate at which the transmitter 98 transmits data may be the same rateat which the sensor circuit 97 obtains signals and/or the processingcircuit 109 provides data or signals to the transmitter 98.Alternatively, the transmitter 98 may transmit data at a slower rate. Inthis case, the transmitter 98 may transmit more than one datapoint ineach transmission. Alternatively, only one datapoint may be sent witheach data transmission, the remaining data not being transmitted.Typically, data is transmitted to the receiver/display unit 46, 48 atleast every hour, preferably, at least every fifteen minutes, morepreferably, at least every five minutes, and most preferably, at leastevery one minute. However, other data transmission rates may be used. Insome embodiments, the processing circuit 109 and/or transmitter 98 areconfigured to process and/or transmit data at a faster rate when acondition is indicated, for example, a low level or high level ofanalyte or impending low or high level of analyte. In these embodiments,the accelerated data transmission rate is typically at least every fiveminutes and preferably at least every minute.

In addition to a transmitter 98, an optional receiver 99 may be includedin the on-skin sensor control unit 44. In some cases, the transmitter 98is a transceiver, operating as both a transmitter and a receiver. Thereceiver 99 may be used to receive calibration data for the sensor 42.The calibration data may be used by the processing circuit 109 tocorrect signals from the sensor 42. This calibration data may betransmitted by the receiver/display unit 46, 48 or from some othersource such as a control unit in a doctor's office. In addition, theoptional receiver 99 may be used to receive a signal from thereceiver/display units 46, 48, as described above, to direct thetransmitter 98, for example, to change frequencies or frequency bands,to activate or deactivate the optional alarm system 94 (as describedbelow), and/or to direct the transmitter 98 to transmit at a higherrate.

Calibration data may be obtained in a variety of ways. For instance, thecalibration data may simply be factory-determined calibrationmeasurements which can be input into the on-skin sensor control unit 44using the receiver 99 or may alternatively be stored in a calibrationdata storage unit 100 within the on-skin sensor control unit 44 itself(in which case a receiver 99 may not be needed). The calibration datastorage unit 100 may be, for example, a readable or readable/writeablememory circuit.

Alternative or additional calibration data may be provided based ontests performed by a doctor or some other professional or by the patienthimself. For example, it is common for diabetic individuals to determinetheir own blood glucose concentration using commercially availabletesting kits. The results of this test is input into the on-skin sensorcontrol unit 44 either directly, if an appropriate input device (e.g., akeypad, an optical signal receiver, or a port for connection to a keypador computer) is incorporated in the on-skin sensor control unit 44, orindirectly by inputting the calibration data into the receiver/displayunit 46, 48 and transmitting the calibration data to the on-skin sensorcontrol unit 44.

Other methods of independently determining analyte levels may also beused to obtain calibration data. This type of calibration data maysupplant or supplement factory-determined calibration values.

In some embodiments of the disclosure, calibration data may be requiredat periodic intervals, for example, every eight hours, once a day, oronce a week, to confirm that accurate analyte levels are being reported.Calibration may also be required each time a new sensor 42 is implantedor if the sensor exceeds a threshold minimum or maximum value or if therate of change in the sensor signal exceeds a threshold value. In somecases, it may be necessary to wait a period of time after theimplantation of the sensor 42 before calibrating to allow the sensor 42to achieve equilibrium. In some embodiments, the sensor 42 is calibratedonly after it has been inserted. In other embodiments, no calibration ofthe sensor 42 is needed.

The on-skin sensor control unit 44 and/or a receiver/display unit 46, 48may include an auditory or visual indicator that calibration data isneeded, based, for example, on a predetermined periodic time intervalbetween calibrations or on the implantation of a new sensor 42. Theon-skin sensor control unit 44 and/or receiver display/units 46, 48 mayalso include an auditory or visual indicator to remind the patient thatinformation, such as analyte levels, reported by the analyte monitoringdevice 40, may not be accurate because a calibration of the sensor 42has not been performed within the predetermined periodic time intervaland/or after implantation of a new sensor 42.

The processing circuit 109 of the on-skin sensor control unit 44 and/oran analyzer 152 of the receiver/display unit 46, 48 may determine whencalibration data is needed and if the calibration data is acceptable.The on-skin sensor control unit 44 may optionally be configured to notallow calibration or to reject a calibration point if, for example, 1) atemperature reading from the temperature probe indicates a temperaturethat is not within a predetermined acceptable range (e.g., 30 to 42° C.or 32 to 40° C.) or that is changing rapidly (for example, 0.2°C./minute, 0.5° C./minute, or 0.7° C./minute or greater); 2) two or moreworking electrodes 58 provide uncalibrated signals that are not within apredetermined range (e.g., within 10% or 20%) of each other; 3) the rateof change of the uncalibrated signal is above a threshold rate (e.g.,0.25 mg/dL per minute or 0.5 mg/dL per minute or greater); 4) theuncalibrated signal exceeds a threshold maximum value (e.g., 5, 10, 20,or 40 nA) or is below a threshold minimum value (e.g., 0.05, 0.2, 0.5,or 1 nA); 5) the calibrated signal exceeds a threshold maximum value(e.g., a signal corresponding to an analyte concentration of 200 mg/dL,250 mg/dL, or 300 mg/dL) or is below a threshold minimum value (e.g., asignal corresponding to an analyte concentration of 50 mg/dL, 65 mg/dL,or 80 mg/dL); and/or 6) an insufficient among of time has elapsed sinceimplantation (e.g., 10 minutes or less, 20 minutes or less, or 30minutes or less).

The processing circuit 109 or an analyzer 152 may also request anothercalibration point if the values determined using the sensor data beforeand after the latest calibration disagree by more than a thresholdamount, indicating that the calibration may be incorrect or that thesensor characteristics have changed radically between calibrations. Thisadditional calibration point may indicate the source of the difference.

The on-skin sensor control unit 44 may include an optional data storageunit 102 which may be used to hold data (e.g., measurements from thesensor or processed data) from the processing circuit 109 permanentlyor, more typically, temporarily. The data storage unit 102 may hold dataso that the data can be used by the processing circuit 109 to analyzeand/or predict trends in the analyte level, including, for example, therate and/or acceleration of analyte level increase or decrease. The datastorage unit 102 may also or alternatively be used to store data duringperiods in which a receiver/display unit 46, 48 is not within range. Thedata storage unit 102 may also be used to store data when thetransmission rate of the data is slower than the acquisition rate of thedata. For example, if the data acquisition rate is 10 points/min and thetransmission is 2 transmissions/min, then one to five points of datacould be sent in each transmission depending on the desired rate forprocessing datapoints. The data storage unit 102 typically includes areadable/writeable memory storage device and typically also includes thehardware and/or software to write to and/or read the memory storagedevice.

The on-skin sensor control unit 44 may include an optional alarm system104 that, based on the data from the processing circuit 109, warns thepatient of a potentially detrimental condition of the analyte. Forexample, if glucose is the analyte, than the on-skin sensor control unit44 may include an alarm system 104 that warns the patient of conditionssuch as hypoglycemia, hyperglycemia, impending hypoglycemia, and/orimpending hyperglycemia. The alarm system 104 is triggered when the datafrom the processing circuit 109 reaches or exceeds a threshold value.Examples of threshold values for blood glucose levels are about 60, 70,or 80 mg/dL for hypoglycemia; about 70, 80, or 90 mg/dL for impendinghypoglycemia; about 130, 150, 175, 200, 225, 250, or 275 mg/dL forimpending hyperglycemia; and about 150, 175, 200, 225, 250, 275, or 300mg/dL for hyperglycemia. The actual threshold values that are designedinto the alarm system 104 may correspond to interstitial fluid glucoseconcentrations or electrode measurements (e.g., current values orvoltage values obtained by conversion of current measurements) thatcorrelate to the above-mentioned blood glucose levels. The analytemonitor device may be configured so that the threshold levels for theseor any other conditions may be programmable by the patient and/or amedical professional.

A threshold value is exceeded if the datapoint has a value that isbeyond the threshold value in a direction indicating a particularcondition. For example, a datapoint which correlates to a glucose levelof 200 mg/dL exceeds a threshold value for hyperglycemia of 180 mg/dL,because the datapoint indicates that the patient has entered ahyperglycemic state. As another example, a datapoint which correlates toa glucose level of 65 mg/dL exceeds a threshold value for hypoglycemiaof 70 mg/dL because the datapoint indicates that the patient ishypoglycemic as defined by the threshold value. However, a datapointwhich correlates to a glucose level of 75 mg/dL would not exceed thesame threshold value for hypoglycemia because the datapoint does notindicate that particular condition as defined by the chosen thresholdvalue.

An alarm may also be activated if the sensor readings indicate a valuethat is beyond a measurement range of the sensor 42. For glucose, thephysiologically relevant measurement range is typically about 50 to 250mg/dL, preferably about 40-300 mg/dL and ideally 30-400 mg/dL, ofglucose in the interstitial fluid.

The alarm system 104 may also, or alternatively, be activated when therate of change or acceleration of the rate of change in analyte levelincrease or decrease reaches or exceeds a threshold rate oracceleration. For example, in the case of a subcutaneous glucosemonitor, the alarm system might be activated if the rate of change inglucose concentration exceeds a threshold value which might indicatethat a hyperglycemic or hypoglycemic condition is likely to occur.

The optional alarm system 104 may be configured to activate when asingle data point meets or exceeds a particular threshold value.Alternatively, the alarm may be activated only when a predeterminednumber of datapoints spanning a predetermined amount of time meet orexceed the threshold value. As another alternative, the alarm may beactivated only when the datapoints spanning a predetermined amount oftime have an average value which meets or exceeds the threshold value.Each condition that can trigger an alarm may have a different alarmactivation condition. In addition, the alarm activation condition maychange depending on current conditions (e.g., an indication of impendinghyperglycemia may alter the number of datapoints or the amount of timethat is tested to determine hyperglycemia).

The alarm system 104 may contain one or more individual alarms. Each ofthe alarms may be individually activated to indicate one or moreconditions of the analyte. The alarms may be, for example, auditory orvisual. Other sensory-stimulating alarm systems may be used includingalarm systems which heat, cool, vibrate, or produce a mild electricalshock when activated. In some embodiments, the alarms are auditory witha different tone, note, or volume indicating different conditions. Forexample, a high note might indicate hyperglycemia and a low note mightindicate hypoglycemia. Visual alarms may use a difference in color,brightness, or position on the on-skin sensor control device 44 toindicate different conditions. In some embodiments, an auditory alarmsystem is configured so that the volume of the alarm increases over timeuntil the alarm is deactivated.

In some embodiments, the alarm may be automatically deactivated after apredetermined time period. In other embodiments, the alarm may beconfigured to deactivate when the data no longer indicate that thecondition which triggered the alarm exists. In these embodiments, thealarm may be deactivated when a single data point indicates that thecondition no longer exists or, alternatively, the alarm may bedeactivated only after a predetermined number of datapoints or anaverage of datapoints obtained over a given period of time indicate thatthe condition no longer exists.

In some embodiments, the alarm may be deactivated manually by thepatient or another person in addition to or as an alternative toautomatic deactivation. In these embodiments, a switch 101 is providedwhich when activated turns off the alarm. The switch 101 may beoperatively engaged (or disengaged depending on the configuration of theswitch) by, for example, operating an actuator on the on-skin sensorcontrol unit 44 or the receiver/display unit 46, 48. In some cases, anactuator may be provided on two or more units 44, 46, 48, any of whichmay be actuated to deactivate the alarm. If the switch 101 and oractuator is provided on the receiver/display unit 46, 48 then a signalmay be transmitted from the receiver/display unit 46, 48 to the receiver98 on the on-skin sensor control unit 44 to deactivate the alarm.

A variety of switches 101 may be used including, for example, amechanical switch, a reed switch, a Hall effect switch, a GiganticMagnetic Ratio (GMR) switch (the resistance of the GMR switch ismagnetic field dependent) and the like. Preferably, the actuator used tooperatively engage (or disengage) the switch is placed on the on-skinsensor control unit 44 and configured so that no water can flow aroundthe button and into the housing. One example of such a button is aflexible conducting strip that is completely covered by a flexiblepolymeric or plastic coating integral to the housing. In an openposition the flexible conducting strip is bowed and bulges away from thehousing. When depressed by the patient or another person, the flexibleconducting strip is pushed directly toward a metal contact and completesthe circuit to shut off the alarm.

For a reed or GMR switch, a piece of magnetic material, such as apermanent magnet or an electromagnet, in a flexible actuator that isbowed or bulges away from the housing 45 and the reed or GMR switch isused. The reed or GMR switch is activated (to deactivate the alarm) bydepressing the flexible actuator bringing the magnetic material closerto the switch and causing an increase in the magnetic field within theswitch.

In some embodiments of the disclosure, the analyte monitoring device 40includes only an on-skin control unit 44 and a sensor 42. In theseembodiments, the processing circuit 109 of the on-skin sensor controlunit 44 is able to determine a level of the analyte and activate analarm system 104 if the analyte level exceeds a threshold. The on-skincontrol unit 44, in these embodiments, has an alarm system 104 and mayalso include a display, such as those discussed below with respect tothe receiver/display units 46, 48. Preferably, the display is an LCD orLED display. The on-skin control unit 44 may not have a transmitter,unless, for example, it is desirable to transmit data, for example, to acontrol unit in a doctor's office.

The on-skin sensor control unit 44 may also include a reference voltagegenerator 101 to provide an absolute voltage or current for use incomparison to voltages or currents obtained from or used with the sensor42. An example of a suitable reference voltage generator is a band-gapreference voltage generator that uses, for example, a semiconductormaterial with a known band-gap. Preferably, the band-gap is temperatureinsensitive over the range of temperatures that the semiconductormaterial will experience during operation. Suitable semiconductormaterials includes gallium, silicon and silicates.

A bias current generator 105 may be provided to correctly biassolid-state electronic components. An oscillator 107 may be provided toproduce a clock signal that is typically used with digital circuitry.

The on-skin sensor control unit 44 may also include a watchdog circuit103 that tests the circuitry, particularly, any digital circuitry in thecontrol unit 44 to determine if the circuitry is operating correctly.Non-limiting examples of watchdog circuit operations include: a)generation of a random number by the watchdog circuit, storage of thenumber in a memory location, writing the number to a register in thewatchdog circuit, and recall of the number to compare for equality; b)checking the output of an analog circuit to determine if the outputexceeds a predetermined dynamic range; c) checking the output of atiming circuit for a signal at an expected pulse interval. Otherexamples of functions of a watchdog circuit are known in the art. If thewatchdog circuit detects an error that watchdog circuit may activate analarm and/or shut down the device.

Receiver/Display Unit

One or more receiver/display units 46, 48 may be provided with theanalyte monitoring device 40 for easy access to the data generated bythe sensor 42 and may, in some embodiments, process the signals from theon-skin sensor control unit 44 to determine the concentration or levelof analyte in the subcutaneous tissue. Small receiver/display units 46may be carried by the patient. These units 46 may be palm-sized and/ormay be adapted to fit on a belt or within a bag or purse that thepatient carries. One embodiment of the small receiver/display unit 46has the appearance of a pager, for example, so that the user is notidentified as a person using a medical device. Such receiver/displayunits may optionally have one-way or two-way paging capabilities.

Large receiver/display units 48 may also be used. These larger units 48may be designed to sit on a shelf or nightstand. The largereceiver/display unit 48 may be used by parents to monitor theirchildren while they sleep or to awaken patients during the night. Inaddition, the large receiver/display unit 48 may include a lamp, clock,or radio for convenience and/or for activation as an alarm. One or bothtypes of receiver/display units 46, 48 may be used.

The receiver/display units 46, 48, as illustrated in block form at FIG.22, typically include a receiver 150 to receive data from the on-skinsensor control unit 44, an analyzer 152 to evaluate the data, a display154 to provide information to the patient, and an alarm system 156 towarn the patient when a condition arises. The receiver/display units 46,48 may also optionally include a data storage device 158, a transmitter160, and/or an input device 162. The receiver/display units 46,48 mayalso include other components (not shown), such as a power supply (e.g.,a battery and/or a power supply that can receive power from a walloutlet), a watchdog circuit, a bias current generator, and anoscillator. These additional components are similar to those describedabove for the on-skin sensor control unit 44.

In one embodiment, a receiver/display unit 48 is a bedside unit for useby a patient at home. The bedside unit includes a receiver and one ormore optional items, including, for example, a clock, a lamp, anauditory alarm, a telephone connection, and a radio. The bedside unitalso has a display, preferably, with large numbers and/or letters thatcan be read across a room. The unit may be operable by plugging into anoutlet and may optionally have a battery as backup. Typically, thebedside unit has a better antenna than a small palm-size unit, so thebedside unit's reception range is longer.

When an alarm is indicated, the bedside unit may activate, for example,the auditory alarm, the radio, the lamp, and/or initiate a telephonecall. The alarm may be more intense than the alarm of a small palm-sizeunit to, for example, awaken or stimulate a patient who may be asleep,lethargic, or confused. Moreover, a loud alarm may alert a parentmonitoring a diabetic child at night.

The bedside unit may have its own data analyzer and data storage. Thedata may be communicated from the on-skin sensor unit or anotherreceiver/display unit, such as a palm-size or small receiver/displayunit. Thus, at least one unit has all the relevant data so that the datacan be downloaded and analyzed without significant gaps.

Optionally, the beside unit has an interface or cradle into which asmall receiver/display unit may be placed. The bedside unit may becapable of utilizing the data storage and analysis capabilities of thesmall receiver/display unit and/or receive data from the smallreceiver/display unit in this position. The bedside unit may also becapable of recharging a battery of the small receiver/display unit.

The receiver 150 typically is formed using known receiver and antennacircuitry and is often tuned or tunable to the frequency or frequencyband of the transmitter 98 in the on-skin sensor control unit 44.Typically, the receiver 150 is capable of receiving signals from adistance greater than the transmitting distance of the transmitter 98.The small receiver/display unit 46 can typically receive a signal froman on-skin sensor control unit 44 that is up to 2 meters, preferably upto 5 meters, and more preferably up to 10 meters or more, away. A largereceiver/display unit 48, such as a bedside unit, can typically receivea receive a signal from an on-skin sensor control unit 44 that is up to5 meters distant, preferably up to 10 meters distant, and morepreferably up to 20 meters distant or more.

In one embodiment, a repeater unit (not shown) is used to boost a signalfrom an on-skin sensor control unit 44 so that the signal can bereceived by a receiver/display unit 46, 48 that may be distant from theon-skin sensor control unit 44. The repeater unit is typicallyindependent of the on-skin sensor control unit 44, but, in some cases,the repeater unit may be configured to attach to the on-skin sensorcontrol unit 44. Typically, the repeater unit includes a receiver forreceiving the signals from the on-skin sensor control unit 44 and atransmitter for transmitting the received signals. Often the transmitterof the repeater unit is more powerful than the transmitter of theon-skin sensor control unit, although this is not necessary. Therepeater unit may be used, for example, in a child's bedroom fortransmitting a signal from an on-skin sensor control unit on the childto a receiver/display unit in the parent's bedroom for monitoring thechild's analyte levels. Another exemplary use is in a hospital with adisplay/receiver unit at a nurse's station for monitoring on-skin sensorcontrol unit(s) of patients.

The presence of other devices, including other on-skin sensor controlunits, may create noise or interference within the frequency band of thetransmitter 98. This may result in the generation of false data. Toovercome this potential difficulty, the transmitter 98 may also transmita code to indicate, for example, the beginning of a transmission and/orto identify, preferably using a unique identification code, theparticular on-skin sensor control unit 44 in the event that there ismore than one on-skin sensor control unit 44 or other transmissionsource within range of the receiver/display unit 46, 48. The provisionof an identification code with the data may reduce the likelihood thatthe receiver/display unit 46, 48 intercepts and interprets signals fromother transmission sources, as well as preventing “crosstalk” withdifferent on-skin sensor control units 44. The identification code maybe provided as a factory-set code stored in the sensor control unit 44.Alternatively, the identification code may be randomly generated by anappropriate circuit in the sensor control unit 44 or thereceiver/display unit 46, 48 (and transmitted to the sensor control unit44) or the identification code may be selected by the patient andcommunicated to the sensor control unit 44 via a transmitter or an inputdevice coupled to the sensor control unit 44.

Other methods may be used to eliminate “crosstalk” and to identifysignals from the appropriate on-skin sensor control unit 44. In someembodiments, the transmitter 98 may use encryption techniques to encryptthe datastream from the transmitter 98. The receiver/display unit 46, 48contains the key to decipher the encrypted data signal. Thereceiver/display unit 46, 48 then determines when false signals or“crosstalk” signals are received by evaluation of the signal after ithas been deciphered. For example, the analyzer 152 in the one or morereceiver/display units 46, 48 compares the data, such as currentmeasurements or analyte levels, with expected measurements (e.g., anexpected range of measurements corresponding to physiologically relevantanalyte levels). Alternatively, an analyzer in the receiver/displayunits 46, 48 searches for an identification code in the decrypted datasignal.

Another method to eliminate “crosstalk”, which is typically used inconjunction with the identification code or encryption scheme, includesproviding an optional mechanism in the on-skin sensor control unit 44for changing transmission frequency or frequency bands upondetermination that there is “crosstalk”. This mechanism for changing thetransmission frequency or frequency band may be initiated by thereceiver/display unit automatically, upon detection of the possibilityof cross-talk or interference, and/or by a patient manually. Forautomatic initiation, the receiver/display unit 46, 48 transmits asignal to the optional receiver 99 on the on-skin sensor control unit 44to direct the transmitter 98 of the on-skin sensor control unit 44 tochange frequency or frequency band.

Manual initiation of the change in frequency or frequency band may beaccomplished using, for example, an actuator (not shown) on thereceiver/display unit 46, 48 and/or on the on-skin sensor control unit44 which a patient operates to direct the transmitter 98 to changefrequency or frequency band. The operation of a manually initiatedchange in transmission frequency or frequency band may include promptingthe patient to initiate the change in frequency or frequency band by anaudio or visual signal from the receiver/display unit 46, 48 and/oron-skin sensor control unit 44.

Returning to the receiver 150, the data received by the receiver 150 isthen sent to an analyzer 152. The analyzer 152 may have a variety offunctions, similar to the processor circuit 109 of the on-skin sensorcontrol unit 44, including 1) modifying the signals from the sensor 42using calibration data and/or measurements from the temperature probe66, 2) determining a level of an analyte in the interstitial fluid, 3)determining a level of an analyte in the bloodstream based on the sensormeasurements in the interstitial fluid, 4) determining if the level,rate of change, and/or acceleration in the rate of change of the analyteexceeds or meets one or more threshold values, 5) activating an alarmsystem 156 and/or 94 if a threshold value is met or exceeded, 6)evaluating trends in the level of an analyte based on a series of sensorsignals, 7) determine a dose of a medication, and 7) reduce noise orerror contributions (e.g., through signal averaging or comparingreadings from multiple electrodes). The analyzer 152 may be simple andperform only one or a small number of these functions or the analyzer152 may perform all or most of these functions.

The output from the analyzer 152 is typically provided to a display 154.A variety of displays 154 may be used including cathode ray tubedisplays (particularly for larger units), LED displays, or LCD displays.The display 154 may be monochromatic (e.g., black and white) orpolychromatic (i.e., having a range of colors). The display 154 maycontain symbols or other indicators that are activated under certainconditions (e.g., a particular symbol may become visible on the displaywhen a condition, such as hyperglycemia, is indicated by signals fromthe sensor 42). The display 154 may also contain more complexstructures, such as LCD or LED alphanumeric structures, portions ofwhich can be activated to produce a letter, number, or symbol. Forexample, the display 154 may include region 164 to display numericallythe level of the analyte, as illustrated in FIG. 23. In one embodiment,the display 154 also provides a message to the patient to direct thepatient in an action. Such messages may include, for example, “EatSugar”, if the patient is hypoglycemic, or “Take Insulin”, if thepatient is hyperglycemic.

One example of a receiver/display unit 46, 48 is illustrated in FIG. 23.The display 154 of this particular receiver/display unit 46, 48 includesa portion 164 which displays the level of the analyte, for example, theblood glucose concentration, as determined by the processing circuit 109and/or the analyzer 152 using signals from the sensor 42. The displayalso includes various indicators 166 which may be activated undercertain conditions. For example, the indicator 168 of a glucosemonitoring device may be activated if the patient is hyperglycemic.Other indicators may be activated in the cases of hypoglycemia (170),impending hyperglycemia (172), impending hypoglycemia (174), amalfunction, an error condition, or when a calibration sample is needed(176). In some embodiments, color coded indicators may be used.Alternatively, the portion 164 which displays the blood glucoseconcentration may also include a composite indicator 180 (see FIG. 24),portions of which may be appropriately activated to indicate any of theconditions described above.

The display 154 may also be capable of displaying a graph 178 of theanalyte level over a period of time, as illustrated in FIG. 24. Examplesof other graphs that may be useful include graphs of the rate of changeor acceleration in the rate of change of the analyte level over time. Insome embodiments, the receiver/display unit is configured so that thepatient may choose the particular display (e.g., blood glucoseconcentration or graph of concentration versus time) that the patientwishes to view. The patient may choose the desired display mode bypushing a button or the like, for example, on an optional input device162.

The receiver/display units 46, 48 also typically include an alarm system156. The options for configuration of the alarm system 156 are similarto those for the alarm system 104 of the on-skin sensor control unit 44.For example, if glucose is the analyte, than the on-skin sensor controlunit 44 may include an alarm system 156 that warns the patient ofconditions such as hypoglycemia, hyperglycemia, impending hypoglycemia,and/or impending hyperglycemia. The alarm system 156 is triggered whenthe data from the analyzer 152 reaches or exceeds a threshold value. Thethreshold values may correspond to interstitial fluid glucoseconcentrations or sensor signals (e.g., current or converted voltagevalues) which correlate to the above-mentioned blood glucose levels.

The alarm system 156 may also, or alternatively, be activated when therate or acceleration of an increase or decrease in analyte level reachesor exceeds a threshold value. For example, in the case of a subcutaneousglucose monitor, the alarm system 156 might be activated if the rate ofchange in glucose concentration exceeds a threshold value which mightindicate that a hyperglycemic or hypoglycemic condition is likely tooccur.

The alarm system 156 may be configured to activate when a single datapoint meets or exceeds a particular threshold value. Alternatively, thealarm may be activated only when a predetermined number of datapointsspanning a predetermined amount of time meet or exceed the thresholdvalue. As another alternative, the alarm may be activated only when thedatapoints spanning a predetermined amount of time have an average valuewhich meets or exceeds the threshold value. Each condition that cantrigger an alarm may have a different alarm activation condition. Inaddition, the alarm activation condition may change depending on currentconditions (e.g., an indication of impending hyperglycemia may alter thenumber of datapoints or the amount of time that is tested to determinehyperglycemia).

The alarm system 156 may contain one or more individual alarms. Each ofthe alarms may be individually activated to indicate one or moreconditions of the analyte. The alarms may be, for example, auditory orvisual. Other sensory-stimulating alarm systems by be used includingalarm systems 156 that direct the on-skin sensor control unit 44 toheat, cool, vibrate, or produce a mild electrical shock. In someembodiments, the alarms are auditory with a different tone, note, orvolume indicating different conditions. For example, a high note mightindicate hyperglycemia and a low note might indicate hypoglycemia.Visual alarms may also use a difference in color or brightness toindicate different conditions. In some embodiments, an auditory alarmsystem might be configured so that the volume of the alarm increasesover time until the alarm is deactivated.

In some embodiments, the alarms may be automatically deactivated after apredetermined time period. In other embodiments, the alarms may beconfigured to deactivate when the data no longer indicate that thecondition which triggered the alarm exists. In these embodiments, thealarms may be deactivated when a single data point indicates that thecondition no longer exists or, alternatively, the alarm may bedeactivated only after a predetermined number of datapoints or anaverage of datapoints obtained over a given period of time indicate thatthe condition no longer exists.

In yet other embodiments, the alarm may be deactivated manually by thepatient or another person in addition to or as an alternative toautomatic deactivation. In these embodiments, a switch is provided whichwhen activated turns off the alarm. The switch may be operativelyengaged (or disengaged depending on the configuration of the switch) by,for example, pushing a button on the receiver/display unit 46, 48. Oneconfiguration of the alarm system 156 has automatic deactivation after aperiod of time for alarms that indicate an impending condition (e.g.,impending hypoglycemia or hyperglycemia) and manual deactivation ofalarms which indicate a current condition (e.g., hypoglycemia orhyperglycemia).

The receiver/display units 46, 48 may also include a number of optionalitems. One item is a data storage unit 158. The data storage unit 158may be desirable to store data for use if the analyzer 152 is configuredto determine trends in the analyte level. The data storage unit 158 mayalso be useful to store data that may be downloaded to anotherreceiver/display unit, such as a large display unit 48. Alternatively,the data may be downloaded to a computer or other data storage device ina patient's home, at a doctor's office, etc. for evaluation of trends inanalyte levels. A port (not shown) may be provided on thereceiver/display unit 46, 48 through which the stored data may betransferred or the data may be transferred using an optional transmitter160. The data storage unit 158 may also be activated to store data whena directed by the patient via, for example, the optional input device162. The data storage unit 158 may also be configured to store data uponoccurrence of a particular event, such as a hyperglycemic orhypoglycemic episode, exercise, eating, etc. The storage unit 158 mayalso store event markers with the data of the particular event. Theseevent markers may be generated either automatically by thedisplay/receiver unit 46, 48 or through input by the patient.

The receiver/display unit 46, 48 may also include an optionaltransmitter 160 which can be used to transmit 1) calibrationinformation, 2) a signal to direct the transmitter 98 of the on-skinsensor control unit 44 to change transmission frequency or frequencybands, and/or 3) a signal to activate an alarm system 104 on the on-skinsensor control unit 44, all of which are described above. Thetransmitter 160 typically operates in a different frequency band thanthe transmitter 98 of the on-skin sensor control unit 44 to avoidcross-talk between the transmitters 98, 160. Methods may be used toreduce cross-talk and the reception of false signals, as described abovein connection with the transmitter 100 of the on-skin sensor controlunit 44. In some embodiments, the transmitter 160 is only used totransmit signals to the sensor control unit 44 and has a range of lessthan one foot, and preferably less than six inches. This then requiresthe patient or another person to hold the receiver/display unit 46 nearthe sensor control unit 44 during transmission of data, for example,during the transmission of calibration information. Transmissions mayalso be performed using methods other than rf transmission, includingoptical or wire transmission.

In addition, in some embodiments of the disclosure, the transmitter 160may be configured to transmit data to another receiver/display unit 46,48 or some other receiver. For example, a small receiver/display unit 46may transmit data to a large receiver/display unit 48, as illustrated inFIG. 1. As another example, a receiver/display unit 46, 48 may transmitdata to a computer in the patient's home or at a doctor's office.Moreover, the transmitter 160 or a separate transmitter may direct atransmission to another unit or to a telephone or other communicationsdevice that alerts a doctor or other individual when an alarm isactivated and/or if, after a predetermined time period, an activatedalarm has not been deactivated, suggesting that the patient may requireassistance. In some embodiments, the receiver/display unit is capable ofone-way or two-way paging and/or is coupled to a telephone line to sendand/or receive messages from another, such as a health professionalmonitoring the patient.

Another optional component for the receiver/display unit 46, 48 is aninput device 162, such as a keypad or keyboard. The input device 162 mayallow numeric or alphanumeric input. The input device 162 may alsoinclude buttons, keys, or the like which initiate functions of and/orprovide input to the analyte monitoring device 40. Such functions mayinclude initiating a data transfer, manually changing the transmissionfrequency or frequency band of the transmitter 98, deactivating an alarmsystem 104, 156, inputting calibration data, and/or indicating events toactivate storage of data representative of the event.

Another embodiment of the input device 162 is a touch screen display.The touch screen display may be incorporated into the display 154 or maybe a separate display. The touch screen display is activated when thepatient touches the screen at a position indicated by a “soft button”which corresponds to a desired function. Touch screen displays are wellknown.

In addition, the analyte monitoring device 40 may include passwordprotection to prevent the unauthorized transmission of data to aterminal or the unauthorized changing of settings for the device 40. Apatient may be prompted by the display 154 to input the password usingthe input device 152 whenever a password-protected function isinitiated.

Another function that may be activated by the input device 162 is adeactivation mode. The deactivation mode may indicate that thereceiver/display unit 46, 48 should no longer display a portion or allof the data. In some embodiments, activation of the deactivation modemay even deactivate the alarm systems 104, 156. Preferably, the patientis prompted to confirm this particular action. During the deactivationmode, the processing circuit 109 and/or analyzer 152 may stop processingdata or they may continue to process data and not report it for displayand may optionally store the data for later retrieval.

Alternatively, a sleep mode may be entered if the input device 162 hasnot been activated for a predetermined period of time. This period oftime may be adjustable by the patient or another individual. In thissleep mode, the processing circuit 109 and/or analyzer 152 typicallycontinue to obtain measurements and process data, however, the displayis not activated. The sleep mode may be deactivated by actions, such asactivating the input device 162. The current analyte reading or otherdesired information may then be displayed.

In one embodiment, a receiver/display unit 46 initiates an audible orvisual alarm when the unit 46 has not received a transmission from theon-skin sensor control unit within a predetermined amount of time. Thealarm typically continues until the patient responds and/or atransmission is received. This can, for example, remind a patient if thereceiver/display unit 46 is inadvertently left behind.

In another embodiment, the receiver/display unit 46, 48 is integratedwith a calibration unit (not shown). For example, the receiver/displayunit 46, 48 may, for example, include a conventional blood glucosemonitor. Another useful calibration device utilizing electrochemicaldetection of analyte concentration is described in U.S. patentapplication Ser. No. 08/795,767, incorporated herein by reference. Otherdevices may be used including those that operate using, for example,electrochemical and colorimetric blood glucose assays, assays ofinterstitial or dermal fluid, and/or non-invasive optical assays. When acalibration of the implanted sensor is needed, the patient uses theintegrated in vitro monitor to generate a reading. The reading may then,for example, automatically be sent by the transmitter 160 of thereceiver/display unit 46, 48 to calibrate the sensor 42.

Additional detailed description of the continuous analyte monitoringsystem, its various components including the functional descriptions ofthe transmitter are provided in U.S. Pat. No. 6,175,752 issued Jan. 16,2001 entitled “Analyte Monitoring Device and Methods of Use”, and inapplication Ser. No. 10/745,878 filed Dec. 26, 2003 entitled “ContinuousGlucose Monitoring System and Methods of Use”, each assigned to theAssignee of the present application, and the disclosures of each ofwhich are incorporated herein by reference for all purposes.

Integration with a Drug Administration System

FIG. 25 illustrates a block diagram of a sensor-based drug deliverysystem 250 according to the present disclosure. The system may provide adrug to counteract the high or low level of the analyte in response tothe signals from one or more sensors 252. Alternatively, the systemmonitors the drug concentration to ensure that the drug remains within adesired therapeutic range. The drug delivery system includes one or more(and preferably two or more) subcutaneously implanted sensors 252, anon-skin sensor control unit 254, a receiver/display unit 256, a datastorage and controller module 258, and a drug administration system 260.In some cases, the receiver/display unit 256, data storage andcontroller module 258, and drug administration system 260 may beintegrated in a single unit. The sensor-based drug delivery system 250uses data form the one or more sensors 252 to provide necessary inputfor a control algorithm/mechanism in the data storage and controllermodule 252 to adjust the administration of drugs. As an example, aglucose sensor could be used to control and adjust the administration ofinsulin.

In FIG. 25, sensor 252 produces signals correlated to the level of thedrug or analyte in the patient. The level of the analyte will depend onthe amount of drug delivered by the drug administration system. Aprocessor 262 in the on-skin sensor control unit 254, as illustrated inFIG. 25, or in the receiver/display unit 256 determines the level of theanalyte, and possibly other information, such as the rate oracceleration of the rate in the increase or decrease in analyte level.This information is then transmitted to the data storage and controllermodule 252 using a transmitter 264 in the on-skin sensor control unit254, as illustrated in FIG. 25, or a non-integrated receiver/displayunit 256.

If the drug delivery system 250 has two or more sensors 252, the datastorage and controller module 258 may verify that the data from the twoor more sensors 252 agrees within predetermined parameters beforeaccepting the data as valid. This data may then be processed by the datastorage and controller module 258, optionally with previously obtaineddata, to determine a drug administration protocol. The drugadministration protocol is then executed using the drug administrationsystem 260, which may be an internal or external infusion pump, syringeinjector, transdermal delivery system (e.g., a patch containing the drugplaced on the skin), or inhalation system. Alternatively, the drugstorage and controller module 258 may provide a the drug administrationprotocol so that the patient or another person may provide the drug tothe patient according to the profile.

In one embodiment of the disclosure, the data storage and controllermodule 258 is trainable. For example, the data storage and controllermodule 258 may store glucose readings over a predetermined period oftime, e.g., several weeks. When an episode of hypoglycemia orhyperglycemia is encountered, the relevant history leading to such eventmay be analyzed to determine any patterns which might improve thesystem's ability to predict future episodes. Subsequent data might becompared to the known patterns to predict hypoglycemia or hyperglycemiaand deliver the drug accordingly. In another embodiment, the analysis oftrends is performed by an external system or by the processing circuit109 in the on-skin sensor control unit 254 or the analyzer 152 in thereceiver/display unit 256 and the trends are incorporated in the datastorage and controller 258.

In one embodiment, the data storage and controller module 258,processing circuit 109, and/or analyzer 152 utilizes patient-specificdata from multiple episodes to predict a patient's response to futureepisodes. The multiple episodes used in the prediction are typicallyresponses to a same or similar external or internal stimulus. Examplesof stimuli include periods of hypoglycemia or hyperglycemia (orcorresponding conditions for analytes other than glucose), treatment ofa condition, drug delivery (e.g., insulin for glucose), food intake,exercise, fasting, change in body temperature, elevated or lowered bodytemperature (e.g., fever), and diseases, viruses, infections, and thelike. By analyzing multiple episodes, the data storage and controllermodule 258, processing circuit 109, and/or analyzer 152 can predict thecourse of a future episode and provide, for example, a drugadministration protocol or administer a drug based on this analysis. Aninput device (not shown) may be used by the patient or another person toindicate when a particular episode is occurring so that, for example,the data storage and controller module 258, processing circuit 109,and/or analyzer 152 can tag the data as resulting from a particularepisode, for use in further analyses.

In addition, the drug delivery system 250 may be capable of providingon-going drug sensitivity feedback. For example, the data from thesensor 252 obtained during the administration of the drug by the drugadministration system 260 may provide data about the individualpatient's response to the drug which can then be used to modify thecurrent drug administration protocol accordingly, both immediately andin the future. An example of desirable data that can be extracted foreach patient includes the patient's characteristic time constant forresponse to drug administration (e.g., how rapidly the glucoseconcentration falls when a known bolus of insulin is administered).Another example is the patient's response to administration of variousamounts of a drug (e.g., a patient's drug sensitivity curve). The sameinformation may be stored by the drug storage and controller module andthen used to determine trends in the patient's drug response, which maybe used in developing subsequent drug administration protocols, therebypersonalizing the drug administration process for the needs of thepatient.

In a further embodiment, the one or more of the receiver/display device256 or the drug administration system 260 may be configured to outputdisplay, using one or more user interface units such as a displayscreen, audible output unit, or a vibratory output unit, theindividual's current monitored analyte levels in addition to one or moretherapy related information substantially simultaneously to assist oraid the individual in his/her therapy management.

For example, the continuously or semi-continuously monitored analytelevels such as glucose levels may be visually displayed on a displayscreen of the receiver/display unit 256 or on a display screen of aninfusion device such an external infusion pump that may be in direct orindirect communication with the receiver/display unit 256. In addition,additional therapy related information such as, for example but notlimited to, insulin action curve associated with the type of insulinbeing or administered, insulin on board information associated with thebasal profile of the individual, one or more historical informationrelated to the insulin administration, or the like. More specifically,in one aspect, the additional therapy related information may besuperimposed for display or provided in an overlay manner with thevisual output of the monitored analyte level.

In this manner, in one embodiment, the user or the patient may beprovided with information related to both the current or real timemonitored continuous or semi-continuous glucose level information, andthe associated insulin related information. In this manner, having boththe information related to the current analyte level as well as theinsulin dosage information in one embodiment may improve or enhancetherapy management. More specifically, as when there is indication thatthe monitored analyte level displayed for the individual or the user isin an upslope indicating an increase in the glucose level, theindividual or the user may decide to take corrective actions such asadministration of insulin dosages, for example, by programming theinfusion device to administer a correction bolus. Without the additionaltherapy related information displayed or otherwise provided to the useror the individual, there may be a tendancy to over-administer theassociated medication such as, for example, resulting in anover-bolusing situation.

By providing substantially real time therapy related information suchas, for example, insulin pharmacodynamics, insulin on board information,basal profile information, hypothetical or calculated insulin actioncurve, and the like concurrently or substantially simultaneously on asingle display unit, for example, in a superimposed or overlay manner,the individual or the user may minimize the risk for hypoglycemia fromover-bolusing or over-dosing than actually necessary due to, forexample, post-prandial monitored analyte levels displayed or otherwiseprovided to the individual or the user. Indeed, in one aspect, byproviding additional information to the individual or the user relatedto the on-going therapy, the potential for inappropriate treatmentattempt or misconceived hypoglycemic or impending hypoglycemic state maybe avoided.

In a further embodiment, the infusion device or the drug delivery system250, for example, may be configured to include a lockout feature thatmay be programmable and includes a temporarily disabling and/or warningindication provided to the user or the individual based on one or moreuser or individual initiated execution attempt related to the operationof the infusion device or the drug delivery system 250.

For example, based on the monitored analyte levels of the user or theindividual and related data processing, under certain circumstances,providing additional safety indications or having a temporary functiondisable feature may be desirable. That is, when it is determined thatthe monitored analyte level is changing beyond a programmed rate ofchange or threshold level, the infusion device or the drug deliverysystem 250 may detect such situations, and also, during this timeperiod, when the user or the individual attempts to deliver oradminister medication such as insulin, in one aspect, the infusiondevice or the drug delivery system 250 (or alternatively, thereceiver/display device 256) may be configured to provide one or moreadditional confirmation request to the user to verify that the user isin fact intending to administer the desired medication dosage.

Alternatively, the infusion device or the drug delivery system 250 maybe configured to temporarily disable the medication delivery when themonitored analyte level deviates from a predetermined threshold level.In this manner, an additional safety feature may be provided in thetherapy management system where based on monitored analyte levels, theindividual or the user may be unable to temporarily administer insulinby, for example, providing a pump lockout feature that disables thebolus or temporarily basal administration function.

In addition, within the scope of the present disclosure, otherparameters may be defined to increase the performance of the therapymanagement system and also in preventing potential hypoglycemia, suchas, for example, the system including a motion detector that may beassociated with the exercise level of the individual or the user, wherethe system may be configured to determine or estimate a variation orfluctuation in the glucose levels after exercise. Additionally, otherparameters may be ascertained by the therapy management system toimprove therapy and potentially minimize the risk for hypoglycemia, suchas modification or one or more insulin administration related thresholdsfor situations where an increase in the risk of potential hypoglycemicstate is determined, or based on a retrospective analysis using adetermined low blood glucose index, or when the infusion device or thetherapy management system detects a user or individual initiateddetermination of a bolus quantity for administration that exceeds apredetermined threshold, and based on a the current or existing basalprofile.

Referring now to the Figures, FIG. 29 is a flowchart illustratingtherapy related management routine in accordance with one embodiment ofthe present disclosure. As shown, monitored or predicted (including, forexample estimated or otherwise calculated or projected analyte relatedinformation based on one or more predefined parameters such as, but notlimited to, patient or user exercise level, physical activity, foodintake, insulin or medication administration) analyte information isoutput (2910). For example, real time analyte information (orestimated/projected analyte information) from the continuous orsemi-continuous glucose monitoring system may be output for graphicaldisplay, for example, on a display unit. Thereafter, a current therapyinformation is retrieved from the therapy management system (which mayinclude the continuous or semi-continuous glucose monitoring system)(2920) such as, current basal profile or level, prior bolus dosagesadministered, insulin on board indicator, and the like. The currenttherapy information may alternatively be determined or calculated basedon one or more individual or patient specific parameters including, forexample, but not limited to physical movement or exercise, carbohydrateamount intake, or anticipated activities and/or food consumption).

Referring back to FIG. 29, the retrieved or determined current therapyinformation is output to the user or the individual so that it isvisually, audibly, vibratorily, or otherwise, provided to the user inconjunction with the outputted monitored or predicted analyteinformation. By way of non-limiting examples, the substantially realtime monitored or predicted analyte information and the current therapyinformation may be displayed on a single display unit of, for example,an infusion device, a data processing unit or receiver of an analytemonitoring system, or both, substantially concurrently, and/or in asuperimposed manner such that both information are readily provided tothe user or the individual in a simple effective manner. For example,the retrieved or determined current therapy information may be an icon,a simple visual indicator such as an arrow or a composite indicator thatis superimposed over a graphical chart or display showing the real timemonitored analyte information. In an alternate embodiment, the therapyinformation displayed may be text information that is provided ordisplayed with the monitored analyte information.

FIG. 30 is a flowchart illustrating therapy related management routinein accordance with one embodiment. Referring to FIG. 30, a rate ofchange of monitored analyte level is detected (3010), and the detectedor predicted (based on a predefined one or more parameters including,such as, for example, a fixed linear function, a curvilinear function,or one or more combination of input patient or user related parameters)rate of change of the monitored analyte level is compared to apredetermined threshold level (3020). Based on the comparison, when itis determined that the detected/predicted rate of change of themonitored analyte level deviates from the predetermined threshold levelby a predefined level or amount, one or more executable therapy relatedfunctions may be disabled or alternatively, a prompt or alert may begenerated and provided to the user or the patient recommending orindicating disabling the one or more executable therapy relatedfunctions. For example, one or more functions related to the insulindosing or administration (such as bolus or temporary basaladministration functions) may be disabled temporarily, or the lockoutfeature for such executable functions may be initiated, or prompted orrecommended to be locked out.

In this manner, in one aspect of the present disclosure, when themonitored analyte level falls below a certain threshold level, theinfusion device administering insulin may be configured to temporarilydisable customized dosing functions to prevent potential for overdosing.

Accordingly, a therapy management device in accordance with oneembodiment includes a display unit, and a processor operatively coupledto the display unit, the processor configured to display one or moreoutput related to an analyte level of an individual, the processorfurther configured to output in a superimposed manner therapy relatedoutput over the displayed one or more outputs related to the analytelevel of the individual.

The output related to an analyte level of the individual may include agraphical display of a continuous monitored glucose level of theindividual.

The therapy related output may include one or more of an insulin actioncurve, an insulin on board information, or a current medication deliveryprofile information.

Also, there may include an insulin delivery unit, where the display unitis coupled to the insulin delivery unit.

Additionally, there may include an analyte monitoring unit, where thedisplay unit is coupled to the analyte monitoring unit.

A method in accordance with another embodiment includes outputting oneor more signals associated with a monitored analyte level of anindividual, determining one or more data associated with one or moretherapy information related to the monitored analyte level, andoutputting in a superimposed manner the determined one or more data overthe outputted one or more signals associated with the monitored analytelevel.

The output one or more signals may include one or more of a line graph,a bar graph, a 2-dimensional visual display, a three-dimensional visualdisplay, an audible output, a vibratory output, or one or morecombinations thereof.

The determined one or more data may be associated with a medicationinformation for the therapy related to the monitored analyte level.

The output one or more signals may be associated with substantially realtime continuously monitored glucose level of the individual.

The determined one or more data output in the superimposed matter mayinclude one or more of an insulin action curve, insulin on boardinformation, or a current medication delivery profile information.

Also, the output one or more signals and the determined one or more datamay be substantially simultaneously displayed on a display unit.

A therapy management device in accordance with still another aspect mayinclude a communication interface configured to receive one or more dataassociated with a monitored analyte level, and a processor coupled tothe communication interface, the processor configured to detect apredetermined rate of change based on the received one or more dataassociated with the monitored analyte level, where the processor isconfigured to disable one or more therapy related functions executableby a user when the detected predetermined rate of change deviates from apredefined threshold level.

The predetermined rate of change may include a decrease in the analytelevel of the user.

The one or more therapy related functions may include one or moremedication administration functions.

The processor may be configured to temporarily disable the one or moretherapy related functions until the detected predetermined rate ofchange substantially falls within the predefined threshold level.

The predefined threshold level may include a hypoglycemic condition oran impending hypoglycemic condition.

A method in accordance with yet still another embodiment may includedetecting a predetermined rate of change of based on one or more dataassociated with the monitored analyte level, and disabling one or moretherapy related functions of a medical device when the detectedpredetermined rate of change deviates from a predefined threshold level.

The disabling may include temporarily disabling one or more executablefunctions of the medical device related to an infusion of a medication.

The disabling may include temporarily disabling the one or more therapyrelated functions of the medical device until the detected predeterminedrate of change substantially falls within the predefined thresholdlevel.

The predefined threshold level may include a hypoglycemic condition oran impending hypoglycemic condition.

A patient with a pre-prandial glucose value of 240 mg/dL and a rapidlyrising glucose, for example, with a rate of glucose change in excess of2 mg dl⁻¹ min⁻¹ may need more insulin than a patient with a relativestable glucose level for example, with a rate of change less than 1 mgdl⁻¹ min⁻¹, or a patient with a rapidly falling glucose level, forexample, with a rate of change less than −2 mg dl⁻¹ min⁻¹. Accordingly,in one aspect, the information on the continuous glucose monitorreceiver regarding the rate of change of glucose may be used in makingmore effective therapeutic decisions regarding insulin administration.

Algorithms in the continuous glucose monitoring system may be configuredto propose insulin dose decisions to the subject using the continuousglucose monitor data incorporating the rate of change data into thetherapeutic decision. The algorithms make insulin dose recommendationsto the user based on both the static and dynamic glucose data. In oneembodiment, the therapeutic recommendation may be based on incorporatingthe rate of change over the preceding period, for example 15 minutes,for example, as indicated by a real time rate of change indicator.

One aspect of the routine may be described as follows. First, thedesired insulin dose level is determined. Thereafter, the determinedinsulin dose level is adjusted (increased or decreased) on the rate ofchange of the monitored glucose level. For example, the determineddesired insulin dose is increased by 10% when the rate of glucose changeindicates a rising glucose level. If the rate of change of the glucoselevel indicates a relatively faster increase (for example, a steeperangle displayed or output to the user of a trend or rate indicator,increase by 20%. On the other hand, if the rate of change of the glucoselevel is minimal, then no adjustment to the desired insulin dose levelis implemented. Finally, if the rate of change of the glucose levelindicates a decrease in the monitored glucose level, the insulin doselevel may be decreased by 10%, and if the rate of decrease is greater,the corresponding insulin dose level may be decreased by 20%.

Alternatively, within the scope of the present disclosure, theadjustment of the insulin dose level may be relative to the insulinrequirements for the patient (for example, based on the patient'sinsulin sensitivity). That is, for a patient with an insulin sensitivityfactor of 20 (mg/dL)/Unit of insulin, an increasing rate of bloodglucose change may result in an increase of 0.75 U of insulin, while apatient with an insulin sensitivity factor of 60 (mg/dL)/Unit of insulinwith the same rate of change of glucose level would only increase by0.15 U of insulin.

In another aspect, projected or predicted values for future glucosebased on the continuous glucose monitoring data may be used as a basisfor insulin dose recommendations. In one aspect, the treatmentrecommendation may change the insulin adjustment by a factor of thedynamic projected glucose (the “Projected Glucose Correction Factor” maybe, for example, one half of the standard insulin correction factor)value and the instantaneous static glucose value. If the instantaneousstatic glucose is 200 mg/dL and the projected glucose value 60 minutesinto the future is 320 mg/dL, the correction bolus or insulin doseamount may be based on the amount of insulin required to reduce both thecurrent glucose and the future glucose.

If the target glucose is 100 mg/dL and, for example, the insulincorrection factor is 1 unit for every 100 mg/dL, the treatment algorithmmay recommend to the patient a 1 unit correction based on the currentvalue plus a 0.6 unit correction based on the projected future value. Atable showing the total calculated insulin is shown below:

Target Glucose: 100 mg/dL Current Insulin Correction Factor(Sensitivity):   1 U per 100 mg/dL Projected (Future) Insulin Correction  1 U per 200 mg/dL Factor (Sensitivity): Current Glucose: 200 mg/dLInsulin Required:   1 U = (200-100) * (1/100) Projected Glucose: 320mg/dL Insulin Required: 0.6 U = (320-200) * (1/200) Total CalculatedInsulin Required: 1.6 U

Exemplary Routines for Insulin Dose Determination

1) Determining Factors Needed to Calculate the Insulin Dose

-   -   a) If at a meal or snack time, determine the carbohydrate        content to be ingested and determine Insulin-to-Carbohydrate        ratio for the patient at that time of day and/or based on the        meal or snack content.    -   b) Determine the insulin sensitivity for the patient at that        time of day and/or based on the meal or snack content.    -   c) Determine the target glucose for the patient at that time of        day and/or based on the meal or snack content.    -   d) Using either a discrete blood glucose measurement or a        continuous glucose measurement, determine the current glucose        concentration of the patient.    -   e) Using a series of continuous glucose measurements (recent        measurements and possibly also measurements determined on        different days in similar conditions), determine the rate of        glucose concentration change.    -   f) Determine a future glucose concentration based on the current        glucose concentration and the rate of glucose concentration        change.    -   g) Determine the future insulin sensitivity for the patient at        that time of day and/or based on the meal or snack content. This        may be related by a ratio, such as 1/2, to the insulin        sensitivity. In addition, or alternatively, the future insulin        sensitivity may be a function of the current glucose        concentration and rate of glucose concentration change.

2) Insulin Dose Determination Example

-   -   a) Using factors from step 1a (above), determine insulin        expected to be needed to compensate for meal or snack.        -   I1, U=(Meal Content, g)*(Insulin-to-Carbohydrate ratio, U/g)    -   b) Using factors from step 1b, 1c, and 1d (above), determine the        insulin expected to be needed to correct the current glucose        concentration to be closer to the target glucose.        -   I2, U=(Current Glucose−Target Glucose, mg/dL)*(Insulin            Sensitivity, U/(mg/dL)). (I2 may be negative.)    -   c) Using factors from step 1e, 1f, and 1g (above), determine the        insulin expected to be needed to correct the Future Glucose        Concentration to be closer to the Target Glucose.        -   I3, U=(Future Glucose−Target Glucose, mg/dL)*(Future Insulin            Sensitivity, U/(mg/dL)). Note I3 may be negative.    -   d) Add the insulin dose components I1, I2, I3, to determine the        necessary insulin dose needed at that time.

The future projected or predicted glucose (“Future GlucoseConcentration”) may be calculated using linear extrapolation methods orother advanced predictive algorithms including auto-regressive methods,time-series methods as well as algorithms based on individualizedphysiological models of a particular subject's insulin-dose response.Different embodiments of the predictive algorithms may rely on differenttime intervals of the prior glucose value in order to make futureprojections (i.e., 30 minute, 1 hour or 2 hours of the immediatepreceding historical data). Still other embodiments may combinepredictive algorithms with individualized physiological models to makeoptimized therapeutic recommendations.

Aspects of the present disclosure may be incorporated with continuousglucose monitoring data into the treatment recommendations provided bythe operating system and user interface of subcutaneous insulin infusionsystems or insulin pumps, or blood glucose meters, or other devicescapable of data communication, processing and user interaction, such as,for example, cellular telephones, personal digital assistants and thelike. The algorithm may be adjusted using the time history of insulinadministered by the insulin pump, or “insulin on board”.

Aspects of the present disclosure includes effective use of the rate ofchange information available from the continuous glucose monitoringsystem in making insulin dose decisions.

In a further aspect, the predicted future glucose value may be matchedto the insulin action curve of the particular insulin used by a patient.As insulin administration typically includes a delay in subcutaneousinsulin absorption as manifest by the onset of insulin action as well asby the time of peak physiological insulin absorption, in one aspect, theinsulin action curve as well as the glucose prediction may be consideredor factored in to further optimize the therapeutic efficacy of therecommended insulin dose.

In a further aspect of the present disclosure, the rate of change of themonitored glucose level may be used in conjunction with certain eventssuch as meal events to improve insulin therapy and address postprandialglycemic excursions. For example, in one aspect, meal related glycemicprofiles may be obtained or determined for a patient or a user based onthe data received from the continuous analyte monitoring system,including, for example, the rate of change of the glucose informationobtained therefrom. With the rate information in conjunction with theglycemic profile surrounding meal events, the corresponding determinedinsulin dosage level (or the basal profile if using an infusion pump,for example) may be modified or adjusted.

In one aspect, real time glucose fluctuation information such as therate of change information, in addition to the prior monitored analytelevels, in the context of the particular events such as meal events thathave impact upon the glycemic level of the user may be used to determineor improve upon the existing insulin therapy. In one aspect, themonitored glucose level may be output to the user as a graphical display(or in any other suitable manner to easily convey the information theuser), where, the real time rate of change information of the glucoselevel is also provided or output to the user (for example, in asuperimposed manner on a display unit). Additionally, event markers ortime of day information including certain events future and/or past,such as meals, exercise, and the like, may be also output.

In this manner, the user or patient may be provided with informationrelated to prior monitored glucose level, current real time informationof the glucose level, and anticipated or projected future glucosemovement direction, some or all of which may be used in conjunction withparticular events such as meal events, to adjust the insulin leveladministered. For example, in the context of meal events, the variousembodiments of the present disclosure provide approaches to addresspostprandial hypoglycemic or postprandial hyperglycemic conditions.

Accordingly, a therapy management device in one aspect includes adisplay unit, and a processor operatively coupled to the display unit,the processor configured to display a carbohydrate intake eventindication, and a graphical representation of a monitored substantiallyreal time analyte level and a rate of change information of themonitored analyte level of an individual approaching the meal eventindication, the processor further configured to output a therapy relatedoutput over the displayed graphical representation of the monitoredanalyte level of the individual.

In aspects of the present disclosure, the device may include an infusionpump, a glucose monitoring device, a controller for the pump and/orglucose monitoring device, a blood glucose meter, a cellular telephone,a personal digital assistant, a personal computer, a handheld electroniccommunication device or any other processor driven devices capable ofstoring data and instructions for execution by the processor, andfurther, configured for wireless or wired communication, and including auser interface such as a display unit, a speaker, a vibratory outputunit, a keypad or keyboard for entering data or instructions, and thelike.

The output related to an analyte level of the individual may include agraphical display of a continuous monitored glucose level of theindividual.

The therapy related output may include one or more of an insulin actioncurve, an insulin on board information, a current medication deliveryprofile information, a modification to the current medication deliveryprofile information, for example.

The device in one aspect may include an insulin delivery unit, where thedisplay unit is coupled to the insulin delivery unit.

The device in another aspect may include an analyte monitoring unit,where the display unit is coupled to the analyte monitoring unit.

A method in a further aspect includes outputting one or more signalsassociated with a monitored analyte level of an individual, the one ormore signals including a substantially real time monitored analyte leveland a rate of change information associated with the monitored analytelevel, outputting a carbohydrate intake event indication, determiningone or more data associated with one or more therapy information relatedto the monitored analyte level and the meal event indication, andoutputting the determined one or more data over the outputted one ormore signals associated with the monitored analyte level and thecarbohydrate intake event indication.

In aspects of the present disclosure, the output one or more signals mayinclude one or more of a line graph, a bar graph, a 2-dimensional visualdisplay, a three-dimensional visual display, an audible output, avibratory output, or one or more combinations thereof.

The determined one or more data may be associated with a medicationinformation for the therapy related to the monitored analyte level.

The carbohydrate intake event indication may be associated with a mealevent of the individual. For example, the meal events may bepredetermined and associated with a respective time of day information.

The determined one or more data may be output in a superimposed matterover the outputted one or more signals associated with the monitoredanalyte level and the carbohydrate intake event indication, thedetermined one or more data including one or more of an insulin actioncurve, insulin on board information, a current medication deliveryprofile information, or a modification to the current medicationdelivery profile information.

The output one or more signals and the determined one or more data maybe substantially simultaneously displayed on a display unit.

A device in accordance with yet another aspect of the present disclosureincludes a communication interface configured to receive one or moredata associated with a monitored analyte level, and a processor coupledto the communication interface, the processor configured to detect acarbohydrate intake event indication, and to detect a predetermined rateof change of the monitored analyte level based on the received one ormore data associated with the monitored analyte level, where theprocessor is further configured to disable one or more therapy relatedfunctions executable by a user when the detected predetermined rate ofchange deviates from a predefined threshold level.

The predetermined rate of change may include a decrease in the analytelevel of the user.

The one or more therapy related functions may include one or moremedication administration functions.

The processor may be configured to temporarily disable the one or moretherapy related functions until the detected predetermined rate ofchange substantially falls within the predefined threshold level.

In a further aspect, the predefined threshold level may include ahypoglycemic condition or an impending hypoglycemic condition.

A method in accordance with still another aspect may include detecting apredetermined rate of change of based on one or more data associatedwith the monitored analyte level within a predetermined time period of ascheduled meal event, and modifying an insulin administration profile ofan insulin infusion device when the detected predetermined rate ofchange deviates from a predefined threshold level.

In another aspect, modifying the insulin administration profile mayinclude suspending the infusion of insulin by the insulin infusiondevice.

Further, modifying the insulin administration profile may includetemporarily suspending the infusion of insulin until the detectedpredetermined rate of change substantially falls within the predefinedthreshold level.

Additionally, the predefined threshold level may include a hypoglycemiccondition or an impending hypoglycemic condition.

In the manner described above, within the scope of the presentdisclosure, in one aspect, postprandial glycemic excursion is addressedto improve insulin therapy for diabetic conditions based on, forexample, real time monitored glucose levels, rate of change of theglucose level information provided, for example, concurrent to themonitored glucose levels, as well as indication of carbohydrate intakeevents such as meal events which are associated with time of dayinformation. Accordingly, in aspects of the present disclosure,postprandial hyperglycemic or hypoglycemic conditions may be addressedto provider improved treatment of diabetic condition based on glycemiccontrol.

Various other modifications and alterations in the structure and methodof operation of this disclosure will be apparent to those skilled in theart without departing from the scope and spirit of the disclosure.Although the disclosure has been described in connection with specificpreferred embodiments, it should be understood that the disclosure asclaimed should not be unduly limited to such specific embodiments. It isintended that the following claims define the scope of the presentdisclosure and that structures and methods within the scope of theseclaims and their equivalents be covered thereby.

1. A management device comprising: an analyte sensor configured forinsertion into a body fluid of a user, the analyte sensor configured tomonitor an analyte level; a display device; and a processor operativelycoupled to the analyte sensor and the display device, the processorconfigured to: determine an initial insulin dose; determine a rate ofchange of the analyte level; and based on the determined rate of change,propose an adjusted insulin dose that is increased or decreased relativeto the initial insulin dose.
 2. The management device of claim 1,wherein the processor is configured to display on the display device therate of change of the analyte level.
 3. The management device of claim1, wherein the adjusted insulin dose is increased by a percentage of theinitial insulin dose if the rate of change of the analyte level isrising.
 4. The management device of claim 1, wherein the adjustedinsulin dose is increased by 10% to 20% of the initial insulin dose ifthe rate of change of the analyte level is rising.
 5. The managementdevice of claim 1, wherein the adjusted insulin dose is decreased by apercentage of the initial insulin dose if the rate of change of theanalyte level is falling.
 6. The management device of claim 1, whereinthe adjusted insulin dose is decreased by 10% to 20% of the initialinsulin dose if the rate of change of the analyte level is falling. 7.The measurement device of claim 1, wherein the adjusted insulin dose isbased on threshold values associated with the rate of change of theanalyte level.
 8. The measurement device of claim 7, wherein thethreshold values are programmable.
 9. The measurement device of claim 1,wherein the increase or decrease relative to the initial insulin dose toarrive at the adjusted insulin dose is customizable.
 10. The measurementdevice of claim 1, wherein the adjusted insulin dose is further based oninsulin sensitivity.
 11. The measurement device of claim 1, wherein theadjusted insulin dose is further based on a predicted future analytelevel.
 12. The measurement device of claim 11, wherein the predictedfuture analyte level is based on a current analyte level and the rate ofchange of the analyte level.
 13. A method comprising: monitoring ananalyte level and proposing an adjusted insulin dose using a managementdevice comprising: an analyte sensor configured for insertion into abody fluid of a user, the analyte sensor configured to monitor ananalyte level; a display device; and a processor operatively coupled tothe analyte sensor and the display device, the processor configured to:determine an initial insulin dose; determine a rate of change of theanalyte level; and based on the determined rate of change, propose anadjusted insulin dose that is increased or decreased relative to theinitial insulin dose.
 14. The method of claim 13, wherein the adjustedinsulin dose is increased by a percentage of the initial insulin dose ifthe rate of change of the analyte level is rising.
 15. The method ofclaim 13, wherein the adjusted insulin dose is increased by 10% to 20%of the initial insulin dose if the rate of change of the analyte levelis rising.
 16. The method of claim 13, wherein the adjusted insulin doseis decreased by a percentage of the initial insulin dose if the rate ofchange of the analyte level is falling.
 17. The method of claim 13,wherein the adjusted insulin dose is decreased by 10% to 20% of theinitial insulin dose if the rate of change of the analyte level isfalling.
 18. The method of claim 13, wherein the adjusted insulin doseis based on threshold values associated with the rate of change of theanalyte level.
 19. The method of claim 18, wherein the threshold valuesare programmable.
 20. The method of claim 18, wherein the increase ordecrease relative to the initial insulin dose to arrive at the adjustedinsulin dose is customizable.